Basal - Ganglia An - Integrative.

BASAL GANGLIA
AN INTEGRATIVE VIEW
Edited by Fernando A. Barrios
and Clemens Bauer
Basal Ganglia An Integrative View

http://dx.doi.org/10.5772/2976
Edited by Fernando A. Barrios and Clemens Bauer
Contributors
Gerry Leisman, Robert Melillo, Frederick R. Carrick, Clivel G. Charlton, M.O. Welcome, V.A.
Pereverzev, Clemens C.C. Bauer, Erick H. Pasaye, Juan I. Romero-Romo, Fernando A. Barrios,
Masahiko Takada, Eiji Hoshi, Yosuke Saga, Ken-ichi Inoue, Shigehiro Miyachi, Nobuhiko
Hatanaka, Masahiko Inase, Atsushi Nambu
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Contents
Preface VII
Chapter 1
Clinical Motor and Cognitive Neurobehavioral

Relationships in the Basal Ganglia 1
Gerry Leisman, Robert Melillo and Frederick R. Carrick
Chapter 2
Fetal and Environmental Basis for

the Cause of Parkinsons Disease 31
Clivel G. Charlton
Chapter 3
Basal Ganglia and the Error Monitoring and Processing

System: How Alcohol Modulates the Error Monitoring
and Processing Capacity of the Basal Ganglia 65
M.O. Welcome and V.A. Pereverzev
Chapter 4
The Integrative Role of the Basal Ganglia 87

Clemens C.C. Bauer, Erick H. Pasaye,
Juan I. Romero-Romo and Fernando A. Barrios
Chapter 5
Organization of Two CorticoBasal Ganglia Loop

Circuits That Arise from Distinct Sectors of
the Monkey Dorsal Premotor Cortex 103
Masahiko Takada, Eiji Hoshi, Yosuke Saga,
Ken-ichi Inoue, Shigehiro Miyachi, Nobuhiko Hatanaka,
Masahiko Inase and Atsushi Nambu
Preface
The study of the function of the Basal Ganglia is a subject of increasing prominence,
not only among neuroscientists, neurologists, psychiatrists and cognitive-scientists but
also for clinical ergonomists, rehabilitation, internal medicine and public health
physicians. This work represents an attempt to bring together diverse scientists who
are interested in a common subject, the Basal Ganglia, nevertheless are situated in
different contexts in the scientific landscape. Basal Ganglia research in the last decade
has been singled out with compelling findings, resulting in new ideas of related
functional networks with other brain structures and internal functions that were not
considered before. Many of these findings come from animal models and brain
functional imaging like fMRI and PET research. These findings have resulted in the
need for new approaches to the study of the Basal Ganglia from animal models to
human brain mapping, translational and clinical practice, therefore, new
interdisciplinary resources regarding Basal Ganglia are needed. All of the contributors
to this volume have published in highly specialized research magazines but want to
pioneer into a multidisciplinary open access work. This volume aims to provide online
access to high-quality research and is an example of leading academics making their
work visible and accessible to diverse audiences around the world.
Fernando A. Barrios and Clemens C. C. Bauer
Neurobiology Institute
National Autonomous University of Mexico,
Mexico
Chapter 1
Clinical Motor and Cognitive Neurobehavioral

Relationships in the Basal Ganglia
Gerry Leisman, Robert Melillo and Frederick R. Carrick
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/55227
1. Introduction
The traditional view that the basal ganglia and cerebellum are simply involved in the
control of movement has been challenged in recent years. One of the pivotal reasons for this
reappraisal has been new information about basal ganglia and cerebellar connections with
the cerebral cortex. In essence, recent anatomical studies have revealed that these
connections are organized into discrete circuits or loops. Rather than serving as a means for
widespread cortical areas to gain access to the motor system, these loops reciprocally
interconnect a large and diverse set of cerebral cortical areas with the basal ganglia and
cerebellum. The properties of neurons within the basal ganglia or cerebellar components of
these circuits resemble the properties of neurons within the cortical areas subserved by these
loops. For example, neuronal activity within basal ganglia and cerebellar loops with motor
areas of the cerebral cortex is highly correlated with parameters of movement, while
neuronal activity within basal ganglia and cerebellar loops with areas of the prefrontal
cortex is more related to aspects of cognitive function. Thus, individual loops appear to be
involved in distinct behavioral functions. Studies of basal ganglia and cerebellar pathology
support this conclusion. Damage to the basal ganglia or cerebellar components of circuits
with motor areas of cortex leads to motor symptoms, whereas damage of the subcortical
components of circuits with non-motor areas of cortex causes higher-order deficits. In this
report, we review some of the new anatomical, physiological and behavioral findings that
have contributed to a reappraisal of function concerning the basal ganglia and cerebellar
loops with the cerebral cortex.
2. The basal ganglia in the context of behavior

The basal ganglia is part of a neuronal system that includes the thalamus, the cerebellum
and the frontal lobes [1]. Like the cerebellum, the basal ganglion was previously thought to
2012 Leisman et al., licensee InTech. This is an open access chapter distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 Basal Ganglia An Integrative View
be primarily involved in motor control. However, recently there has been much written
about and the role of the basal ganglia in motor and cognitive functions has now been well
established [2-6].
Figure 1. The basal ganglia that clinical include clinically includes subthalamic nucleus & substantia
nigra whose component structures are highly interconnected. The striatum is associated with input
signal and output associated with the globus pallidus & substantia nigra.
The basal ganglia is located in the diencephalon and is made up of five subcortical nuclei
(represented in Fig.1): globus pallidus, caudate, putamen, substantia nigra and the
subthalamic nucleus of Luys. The basal ganglia is thought to have expanded during the
course of evolution as well and is therefore divided into the neo and paleostriatum. The
paleostriatum consists primarily of the globus pallidus, which is derived embryologically
from the diencephalon. During the course of its development it further divides into two
distinct areas, the external and internal segments of the globus pallidus. The neostriatum is
made up of two nuclei, the caudate and putamen. These two nuclei are fused anteriorly and
are collectively known as the striatum. They are the input nuclei of the basal ganglia and
they are derived embryologically from the telencephalon. The subthalamic nucleus of Luys
lies inferiorly to the thalamus at the junction of the diencephalon and the mesencephalon or
midbrain. The substantia nigra lays inferiorly to the thalamus and has two zones similar to
the globus pallidus. A ventral pole zone called pars reticulata exists as well as a dorsal
darkly pigmented zone called the pars compacta. The pars compacta contains dopaminergic
neurons that contain the internum. The globus pallidus internum and the pars reticulata of
the putamen are the major output nuclei of the basal ganglia. The globus pallidus internum
and the pars reticulata of the putamen are similar in cytology, connectivity, and function.
These two nuclei can be considered to be a single structure divided by the internal capsule.
Their relationship is similar to that of the caudate and putamen. The basal ganglia is part of
Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 3
the extrapyramidal motor system as opposed to the pyramidal motor system that originates
from the sensory-motor cerebral cortex. The pyramidal motor system is responsible for all
voluntary motor activity except for eye movement. The extrapyramidal system modifies
motor control and is thought to be involved with higher-order cognitive aspects of motor
control as well as in the planning and execution of complex motor strategies, as well as the
voluntary control of eye movements. There are two major pathways in the basal ganglia, the
direct pathways, which promote movement, and the indirect pathways, which inhibit
movement.
The basal ganglia receive afferent input from the entire cerebral cortex but especially from
the frontal lobes. Almost all afferent connections to the basal ganglia terminate in the
neostriatum (caudate and putamen). The neostriatum receives afferent input from two
major sources outside of the basal ganglia, the cerebral cortex (cortico-striatal projections),
and the intralaminar nucleus of the thalamus. The corticostriatal projections contain
topographically organized fibers originating from the entire cerebral cortex. An important
component of that input comes from the centro-median nucleus from the thalamus and
terminates in the putamen. Because the motor cortex of the frontal lobes projects to the
centro-median nucleus, this may be an additional pathway by which the motor cortex can
influence the basal ganglia. The putamen appears to be primarily concerned with motor
control whereas the caudate appears to be involved in the control of eye movements and
certain cognitive functions. The ventral striatum is related to limbic function, and therefore
may affect autonomic and emotional functions.
The major output of the basal ganglia arises from the internal segment of the globus pallidus
and the pars reticulata of the substantia nigra. The nuclei project in turn to three nuclei in
the thalamus, the ventral lateral nuclei, the ventral anterior nuclei, and the mesio-dorsal
nuclei, as well as the anterior thalamic nuclei. Internal segments of the globus pallidus
project to the centro-median nucleus of the thalamus. Striatal neurons may be involved with
gating incoming sensory input to higher motor areas such as the intralaminar thalamic
nuclei and premotor cortex that arise from several modalities to coordinate behavioral
responses. These different modalities may contribute to the perception of sensory input [7]
leading to motor response. The basal ganglia are directed, in a way similar to the
cerebellum, to premotor and motor cortices as well as the prefrontal cortex of the frontal
lobes.
Experiments where Herpes simplex virus 1 (HSV-1) was administered into the dorsal lateral
prefrontal cortex of monkeys to determine its axonal spread or connection, labeled the
ipsilateral neurons in the internal segments of the globus pallidus and the contralateral
dentate nucleus of the cerebellum [8]. It is therefore thought that this may show a role of
both the cerebellum and basal ganglia in higher cognitive functions associates with the
prefrontal cortex. This would also substantiate a cortico-striato-cerebello-thalamo-cortical
loop, which would have a cognitive rather than motor function, exemplified in Fig. 2 below.
The putamen is also thought to connect to the superior colliculus through nondopaminergic axons that forms an essential link in voluntary eye movement.
Cerebral cortex
Motor areas
Caudate/Putamen
Subthalamic
nucleus
Spinal
cord
Globus
pallidus
(external)
Excitatory
glutamate
dopamine
Substantia
nigra pars
compacta
Inhibitory
GABA
Thalamus
Globus
pallidus
(internal)
Substantia
nigra pars
reticulata
Figure 2. Circuitry of the basal ganglia. The cerebral cortex (and thalamus) projects to the striatum
(excitatory pathways). The striatum also receives dopaminergic projections from the substania nigras
pars compacta (SNc). The striatum inhibits the globus pallidus (GP) as well as the substantia nigras
pars reticulata (SN pr). The STN sends excitatory projections to the GPi, GPe & SNpr. GPi or SN pr
inhibits (GABAergic) the thalamus. The thalamus projects to the cortex (also excitatory). The direct path
leads to less inhibition of the thalamus, (i.e. the striatum inhibits GPi which in turn inhibits its normal
(inhibitory) action on the thalamus, thus leading to greater excitation from the thalamus to the cortex.
This allows for sustain actions or initiation of action. The indirect path excites the GPi thereby
increasing its inhibition of the thalamus and thus suppresses unwanted movements.
Figure 3. Cortical-basal ganglia pathways. All regions of cerebral cortex project to the basal ganglia, but
output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary
motor cortex.
It is thought that normal basal ganglia function results from a balance of the direct and
indirect striatal output pathway and different involvement of these pathways account for
hyperkinesia or hypokinesia observed in disorders of the basal ganglia [9]. Hypokinesia is a
disinhibition or increase in spontaneous movement (tics, tremors). It is thought that
hypokinesia and hyperkinesia may relate to hypoactive behavior and hyperactive behavior
associated with subcortical hypo-stimulation or hyper-stimulation of medial and orbitofrontal cortical circuits [10]. It is important to review these connections further to
understand the role of basal ganglia in control of cognitive function.
Five fronto-subcortical circuits unite regions of the frontal lobe (the supplementary motor
area; frontal eye fields; dorsolateral, prefrontal, orbito-frontal and anterior cingulate
cortices) with the striatum, globus pallidus and thalamus in functional systems that mediate
volitional motor activity, saccadic eye movements, executive functions, social behavior and
motivation [10,11].
3. Direct and indirect pathways

Five major cortical to subcortical loops exist that make up cortico-striatal pathways. All
cortical pathways initiate the direct and indirect pathways with the basal ganglia through
excitatory glutamatergic cortico-striatal fibers (the general circuitry is described in Fig. 3 and
direct and indirect pathways exemplified in Fig. 4). The direct pathway from the striatum
sends GABA fibers (associated with dopamine receptors) from the striatum to the globus
pallidus and putamen. The indirect pathway sends inhibitory GABA/enkephalin fibers
(associated with D2 dopamine receptors) from the striatum to the globus pallidus. Indirect
pathways then continue with inhibitory GABA fibers from the globus pallidus to the
subthalamic nucleus of Luys. Indirect excitatory glutamatergic fibers then connect from the
subthalamic nucleus to the globus pallidus and putamen. The basal ganglia then sends
inhibitory outflow by GABA fibers from the globus pallidus and putamen to specific
thalamic nuclei. The thalamus has excitatory fibers that return to the cortex [10].
Abnormalities of direct and indirect pathways result in different pathological functions.
The nature of the balance between components of these pathways is described in greater
detail in the section below and described in Figs. 3-5. Hyperkinetic disorders (increased
movement) are thought to be a selective loss of GABA/enkephalinergic intrinsic striatal
neurons projecting to the lateral globus pallidus and substantia nigra. This results in
decreased inhibitory stimulation to the thalamus leading to increased activity of the
excitatory glutamatergic thalamocortical pathways and in turn greater neuronal activity in
the premotor-motor and supplementary motor cortices [12]. The result is over-facilitation of
motor programs resulting in increased motor activity. Hypokinetic disorders (decreased
movement) are associated with decreased dopaminergic nigrostriatal stimulation from the
substantia nigra to the striatum. This results in both excess outflow of the indirect striatal
pathway and an inhibited direct striatal pathway. Both of these pathways increase thalamic
inhibition and therefore decrease thalamocortical stimulation of motor cortical areas
resulting in hypokinesia or decreased output of the frontal cortex [10,13,14]. It is possible
Functional Organization of the Basal Ganglia
Cortex
Motor Cortex
Globus
pallidus
external
Subthalamic
nucleus
Direct pathway
Indirect pathway
Basal Ganglia
Striatum
Globus
pallidus
internal/
substantia
nigra pars
reticulata
Thalamus
Direct Pathway: Increases motor output

Indirect Pathway: Decreases motor output
Figure 4. Direct and Indirect pathways. Direct pathway runs: CortexstriatumGPi

thalamuscortex. Two links are excitatory & two inhibitory, so the net effect of the whole
sequence is excitatory. The cortex excites itself via the direct pathway. The Indirect pathway runs:
cortexstriatumGPe STNGpithalamuscortex. Three links are inhibitory and two excitatory,
so the net effect of the sequence is inhibitory: The cortex inhibits itself via the indirect pathway. The
total effect of basal ganglia upon the cortex results from complex interplay between these two
pathways.
that the difference between hypokinetic and hyperkinetic syndromes may be different only
in the timing and or the severity of the dysfunction. In this model, decreased thalamic
excitation of the frontal cortex results in decreased excitation of the cortico-striatal fibers of
the neostriatum. The neostriatum therefore decreases its inhibitions of the globus pallidus.
There is then increased inhibition of the thalamocortical pathways leading to progressive
hypokinesia. Eventually the lack of striatal inhibition of the globus pallidus results in its
metabolic dysfunction and the rapid loss of GABA neurons. This can then result in
decreased inhibition of thalamocortical pathways causing a sudden onset of hyperkinesia
(increased movement) with the increased thalamic firing of the frontal cortex. There also
appear to exist cognitive symptoms that parallel the motor effects. Previous studies have
shown that patients with hyperkinetic, hypokinetic, Tourettes, and Obsessive-Compulsive
disorders may exhibit neuropsychiatric disturbances such as apathy, depression, agitation,
or excitability [15-20].
Figure 5. Circuit diagram for direct & indirect pathways. Neurotransmitters: Ach, acetylcholine; DA,
dopamine; Glu, glutamate; Enk, enkaphalin; SP, substance P. Nuclei: SNc, substantia nigra pars
compacta; SNr, substantia nigra pars retriculata; GPe, globus pallidus pars externa; GPi, globus pallidus
pars interna; STN, subthalamic nucleus; VL, ventral lateral nucleus; VA, ventral anterior nucleus.
4. Clinical behavioral implications of pathway activity balance

Most disorders that involve the basal ganglia produce dysfunction by promoting an
imbalance between the direct and indirect pathways. An increase in the relative activity in
the direct pathways results in hyperkinetic movements and behaviors. This has been
hypothesized to be a result of decreased activity of the indirect or increased activation of the
direct pathway [11,13,14]. Increased relative activity in the indirect pathway is associated
with hypokinetic movement and behaviors [21-23]. The majority of input to the basal
ganglia comes from a top down direction through the five loops from the frontal lobe [24]
referenced above. The premotor and supplementary motor areas, frontal and supplemental
eye fields, the orbital frontal cortex, the dorsal lateral prefrontal cortex, and the anterior
cingulate all connect into the basal ganglia governing voluntary motor activity, voluntary
saccadic eye movement, social behavior, executive function, and motivation. These are then
connected to various areas within the thalamus and back to the cortex. The indirect pathway
increases the output of the globus pallidus internis [25,26] and increases the inhibition of the
thalamus and motor activity or behaviors. Increase in direct pathway function inhibits the
output of the globus pallidus thereby promoting increased movement and cognitive
behaviors.
One of the main clinical questions especially in the absence of any obvious damage or
pathology is what promotes a functional imbalance between these pathways (represented in
Fig. 5). Various disorders such as ADHD, Tourettes, OCD among other are known to
involve the basal ganglia. In these disorders there is hyperkinetic movement and or
behaviors that coincide with the particular loop that is affected, but in all cases the increase
seems to be in the direct loop not the indirect loop [9,11,17-21].
The principle question here is why these disorders would target an increase in this pathway
in particular. One of the differences may have to do with the receptors that are involved in
one pathway more than the other. The D1 receptor is known to be found in the direct
pathway while the D2 receptor is found in the indirect loop. The nigrostriatal pathway is
believed to help promote movement through its dopaminergic activity in the zona compacta
by connecting to the Putamen and increasing the activity of the D1 receptor and inhibiting
the D2 receptor [27]. Parkinsons Disease which is manifest as a hypokinetic disorder is, in
part, related to this loss of increased activity to the direct pathway following degeneration of
the dopaminergic neurons in the zona compacta. Using this as an example, other pathways
that connect and enhance one receptor over the other is a way to functionally bias
complementary pathways. We can understand the direct pathway as a behavioral activating
pathway and the indirect as the behavioral inhibiting pathway [28]. This description can
also been applied to the two cerebral hemispheres and their role in behavioral control. The
left hemisphere is thought to promote approach behaviors [29,30], motor activity [24],
intention [29] and positive emotions [30]. The right hemisphere is thought to promote
withdrawal behavior [29], sensory and attentional activity [29], and negative affect [29]. The
left hemisphere promotes motor and increases behavioral activity and motivation while the
right hemisphere is known to do the opposite [29]. Therefore it is reasonable to assume that
when utilizing top-down control, the two cerebral hemispheres may differentially enhance
or inhibit motor activity and cognitive behavior.
The premotor areas and frontal eye fields increase volitional as well as involoutional motor
activity and saccadic eye movements [31], the left orbital frontal cortex increases social
motivation and awareness [29], the left dorsal lateral prefrontal cortex increases executive
and cognitive function [24,30], while the left anterior cingulate increases motivation [29].
The right hemisphere decreases or inhibits those same pathways [32]. This would give even
greater top-down control over these behaviors and it would make sense that this is done by
enhancing the direct or indirect pathway.
The left hemisphere would promote and increase movement and behavior by selectively
increasing the direct pathways perhaps by favoring the D1 receptors in the caudate and or
putamen. The right hemisphere could promote the indirect pathway function by selectively
enhancing or stimulating the D2 receptors in these same areas. Since many of the
hyperkinetic disorders like ADHD, Tourettes and OCD have all been associated with a
decreased function of the right hemisphere and an increased function of left hemisphere
activity [24,33,34] that would also seem to fit with the argument that a decrease in right
hemisphere function would be associated with an increase in left hemisphere function and
enhancement of the direct pathway and the D1 receptor promoting hyperkinetic movement
and behaviors.
The right hemisphere could also have stronger connections to the subthalamic nucleus of
Luys which would also enhance the indirect pathway whereas stronger left hemisphere
connections to the caudate and putamen may also enhance direct pathway activation over
indirect [14]. There are other receptors that could be selectively targeted by one hemisphere
more than the other. The hemispheres are well documented to have this type of differential
top-down control over other functions such as the immune system [35], autonomic system
[30] as well as top down control of sensory processing at the thalamic level with corticothalamic fibers outnumbering thalamocortical fibers by a 10 1 ratio [36].
The recent discovery of a hyperdirect pathway [37] confirms that this hemispheric
relationship exists and in fact it seems to affect both pathways as we described. The right
hemisphere generally is known to be more involved with behavioral inhibition whereas the
left hemisphere generally is involved in behavioral excitation. This effect in part seems to be
due to the relationship between the cortex, and the prefrontal cortex and basal ganglia. The
five primary loops from the frontal lobe to the basal ganglia as we described include the
premotor cortex for movement, the orbital frontal cortex for social behavior, the dorsolateral
prefrontal cortex controls executive function, the anterior cingulate regulates motivation,
and the frontal eye fields control saccadic eye movements. Together these loops help to
regulate all human behaviors. The left hemisphere control appears to have an excitatory
influence whereas the right hemisphere seems to subserve primarily an inhibitory control of
these functions. This appears to mainly be accomplished by the hyperdirect pathway of the
right hemisphere. The hyperdirect pathway accomplishes this through its influence on the
D2 receptor which initiates the indirect pathway. This pathway increases the inhibitory
output of the GPi and its influence on the thalamic relay nuclei.
The second way that the right hemisphere exerts this inhibitory control is through the
hyperdirect connection from the inferior frontal gyrus directly through an excitatory
glutamatenergic connection to the subthalamic nucleus of Luys. This increases the output of
excitatory connections to the Gpi and an inhibitory connection to the GPe, which is
inhibitory to the SNL. This also activates the indirect pathway increasing the inhibitory
output of the GPi to the thalamus. Without this activity, the left hemisphere will have a
relatively increased output to the D1 receptor activating the direct pathway, which
decreases the output of the GPi through its inhibitory GABAnergic connections. This, in
turm, decreases the inhibition of the thalamic nuclei thereby increasing activity in these
prefrontal loops. The clinical implications of this are significant especially in functional
lesions of the brain where there are no anatomic lesions but rather a primary imbalance
between the direct and indirect pathways.
A functional imbalance and/or a functional disconnection between the two hemispheres,

that may be the result of an activation imbalance in the cortex between the two hemispheres,
can lead to an imbalance in these loops producing either hyperkinetic or hypokinetic
disorders. This would explain why symptoms of hyperkinetic disorders like ADHD also
seem to be associated with a decrease in many right hemisphere functions along with
relative increases in left hemisphere functions. This also would mean that therapeutically
increasing the activation through target stimulation to one hemisphere and possibly to one
or more dysfunctioning basal ganglionic loops may help to restore a balance and temporal
coherence between the hemispheres and between the direct and indirect loops.
For instance if someone is experiencing symptoms of OCD they have obsessions and
compulsions in the absence of a specific lesion in the basal ganglia and specifically in the
indirect pathway, this may be explained by decreased activation in the loops that involve
the premotor cortex which control motor activity (compulsions) and the dorsolateral
prefrontal cortex which controls executive functions, planning and behavior (obsessions) on
the right hemisphere. This may result in a relative increase in those same loops on the left
hemisphere leading to a relative increase of the direct pathway over the indirect pathway in
those specific loops leading to OCD symptoms.
If this is the case then providing specific targeted stimulation to the premotor areas and the
dorsolateral prefrontal cortex on the right hemisphere with the proper frequency, intensity
and duration may produce an equilibration between the loops in those hemispheres and in
the direct and indirect pathways. This may provide the best therapeutic option because it is
specific, noninvasive and can provide long term correction which would be the ultimate
goal.
5. Dynamic inter-regional effects

Disconnection syndromes were originally conceptualized as a disruption of communication
between different cerebral cortical areas [30,31]. Schmahmann and Pandya [38] in an elegant
review, indicate that the concept could be expanded. In overviewing their anatomical
studies of monkeys, they found that efferent fibers emanate from every cortical area, and are
directed with topographic precision via association fibers to ipsilateral cortical areas,
commissural fibers to contralateral cerebral regions, striatal fibers to basal ganglia, and
projection subcortical bundles to thalamus, brainstem and/or pontocerebellar system. They
concluded that cortical areas are definable by their patterns of subcortical and cortical
connections.
In applying their findings to humans, they note that motor, cognitive and neuropsychiatric
disorders in patients with basal ganglia lesions, as well as those of the thalamus, or
cerebellum, tend to mimic deficits resulting from cortical lesions, with qualitative
differences between the manifestations of lesions in functionally related areas of cortical and
subcortical nodes. These basal ganglia based behavioral conditions are viewed by
Schmahmann and Pandya as disconnection syndromes reflecting loss of the contribution of
subcortical nodes to the distributed neural circuits. They concluded that neural architecture
determines function, i.e., each architectonically distinct cortical and subcortical area
contributes a unique transform, or computation, to information processing as suggested by
Leisman and Melillo [30]. Anatomically precise and segregated connections between nodes
define behavior and association fiber tracts that link cerebral cortical areas with each other
enable the cross-modal integration required for evolved complex behaviors.
Co-contration of muscle groups is realistically the co-activation of competing motor
programs that serves as a fundamental mechanism used to achieve postural
stabilization. Thus motor and cognitive signs associated with basal ganglionic lesions
should also have a postural component that aids clinicians in the identification of lesions as
well as providing a window for outcome observations when dealing with cognitive strategy
efficacy.
The effective function involving the basal ganglia is traditionally thought to be achieved via
a balance of excitation and inhibition of competing motor programs. In the context of this
review, cognitive and motor functions need to be linked with postural control
systems. These systems are known to be dynamic, rather than static. Hyperkinetic
dystonias, for example, reflect excessive function of dynamic postures, rather than abnormal
movements. Anne Blood [39] has suggested that the range of functional roles served by the
postural system is hypothesized to include direct control of movement, suggesting a
postural basis for task-specific dystonias. Further, by defining posture as a neural system
that maintains body stabilization, it can be shown that the range of mechanical means of
implementing stabilization, including co-contraction of antagonistic muscles, matches the
range of presentations of dystonia reflecting abnormal integration in the basal ganglia.
Inhibitory influences that stabilizing mechanisms exert on movement, suggest that the
broad functional role of posture may be the function served by the indirect pathway of the
basal ganglia. Specifically, the integrated pathway that centrally coordinates function of the
distributed network of brain regions controlling posture and, in conjunction with the direct
pathway, coordinates posture and movement. Postural systems are probably involved in
cognition as well as the motor volitional and reflexogenic parameters of basal ganglionic
influence. The involvement of posture in the basal ganglia and behavioral relationships is
further supported by Marsden and Rothwell [41] who noted that co-contraction is
realistically the co-activation of competing motor programs that serves as a fundamental
mechanism used to achieve postural stabilization.
Numerous other investigators have recently begun to notice the relationship of posture to
basal ganglia and cognitive function serving as a basis for the clinical discussions in the
subsequent section. Mitra and colleagues [40] noted that the performance of a cognitive task
while maintaining upright stance is associated with changes in body sway depending on
tasks and experimental conditions. As increased sway is taken to indicate loosened postural
control the precise impact of cognitive load on postural stability has remained unclear.
These investigators noted that body sway increased during cognitive tasks while quiet
standing but not while performing a visuo-postural alignment task suggesting that
constraints placed on posture control by supra-postural task goals may significantly alter
interactions between posture control and cognitive task.
Fujiwara and associates [42] investigated the effect of neck flexion on discriminative and
cognitive processing in postural control during bilateral arm movement while standing,
using event-related potential (ERP) and electromyogram. They noted significant positive
correlations with neck flexion and P3 latency and anterior deltoid reaction time, and
between N2 latency and the onset time of erector spinae, suggesting that with neck flexion,
attention allocation to discriminative and cognitive processing increases, and the processing
speed increases with shortening of reaction time in focal muscles.
Thus there is enough preliminary evidence to indicate that motor and cognitive signs
associated with basal ganglionic lesions should also have a postural component that would
aid clinicians in the identification of lesions as well as providing a window for outcome
observations when dealing with cognitive strategy efficacy.
6. Clinical implications
It has been hypothesized that neuropsychiatric symptoms exhibited by patients with basal
ganglia disorders are a consequence of an involvement of fronto-striatal connections. In
addition to expressing contrasting motor dysfunction patterns, these disorders would also
differ in the presenting psychiatric symptoms [10]. In this study patients with Huntingtons
disease (hyperkinetic) and Parkinsons disorder (hypokinetic) were observed to determine if
they would present with hyperactive behavior (agitation, isolation, euphoria, or anxiety)
and hypokinetic behavior (apathy) respectively. The results of this study demonstrated that
patients with Huntingtons (hyperkinetic) more frequently exhibited hyperactive behaviors
such as agitation, irritability, euphoria, and anxiety whereas patients with Parkinsons
(hypokinetic) frequently displayed hypoactive behavior (high levels of apathy). The
investigators thought that in Huntingtons, these behaviors result from excitatory
subcortical output through the medial and orbito-frontal circuits to the pallidum, thalamus,
and cortex as well as premotor and motor cortex. In contrast, patients with Parkinsons
(hypoactive) in whom apathy is present were thought to demonstrate these behaviors as a
consequence of hypo-stimulation of frontal subcortical circuits resulting from damage to
several integrated nuclei (putamen, striatum and globus pallidus) [14,43,44].
It had been previously noted that patients with Huntingtons and other hyperkinetic
disorders like Tourettes exhibit mania, OCD, and intermittent explosive disorder [45,46-48].
PET studies of Huntingtons patients without hyperactive behavior have shown frontal
metabolism to be normal but with decreased caudate and putamen metabolism [49,50].
However is it thought that normal frontal metabolism in Huntingtons may result from a
coexistent neurological degeneration and the resultant thalamo-frontal hyper-stimulation.
This may result in normal appearing frontal-cortical regional blood flow even when overt
prefrontal type cognitive defects are manifested. This suggests that in this case, a
dysfunctional prefrontal cortex may appear to be at baseline levels that appear normal when
in fact the prefrontal cortices may be over stimulated by the thalamus. [51,52]. In fact, it was
noted that with further atrophy of the caudate there was increased fronto-cortical
metabolism while the patient performed cognitive tasks (set-shifting) and a greater increase
in cerebral metabolism over baseline. The poorer the subject performed on cognitive tasks,
the greater the cortical activation. [51,52]. It has been speculated that in early Huntingtons
when there are no frontal lobe lesions, a relative balance between frontal and increased
thalamic functions may explain behavioral symptoms [10].
PET scans of patients with Parkinsons have also provided support that frontal-subcortical
connections are disrupted by subcortical dysfunction showing decreased glucose
consumption in frontal cortex, and decrease nigrostriatal D2 receptor uptake ratios [53,54].
Researchers at Stanford University may have observed similar results in children with
ADHD also known as childhood hyperkinetic disorder [55]. The Stanford study used
functional MRI to image the brains of boys between the ages of 8 and 13 while playing a
mental game. Ten of the boys were diagnosed with ADHD and six were considered normal.
When the boys were tested there appeared to be a clear difference in the activity of the basal
ganglia with the boys with ADHD having less activity in that area than the control subjects.
After administering methylphenidate, the participants were scanned again and it was found
that boys with ADHD had increased activity in the basal ganglia whereas the normal boys
had decreased activity in the basal ganglia. Interestingly, the drug improved the
performance of both groups to the same extent.
This may be a similar finding as the PET scans on patients with hyperactivity disorder,
where normal appearing frontal metabolism existed with decreased caudate and putamen
metabolism [56]. Methylphenidate, a dopamine reuptake inhibitor, may increase function in
a previously dysfunctional basal ganglia whereas raising dopamine levels in normal
individuals would most likely result in decreased activity of the basal ganglia to prevent
overproduction of dopamine. The previously dysfunctional basal ganglia would have most
likely resulted in decreased frontal metabolism with increased thalamo-cortical firing; this
would result in decreased cognitive function with increased hyperkinetic (hyperactive)
behavior. Increasing dopamine levels may increase frontal metabolism due to increased
activity of the striatum with decreased firing of the globus pallidus thereby inhibiting
thalamo-cortical firing decreases which in turn decreases hyperkinetic behavior. This would
make sense based on the findings of fMRI before and after, and the fact that both groups
showed equal improvement in performance.
7. Basal ganglia in obsessive compulsive disorder

Cognitive and brain maturational changes continue throughout late childhood and
adolescence. During this time, increasing
cognitive control over behavior enhances the
voluntary suppression of reflexive/impulsive response tendencies [29,30]. We presently
have the capacity to characterize changes in brain activity during cognitive development.
Optimized top-down modulation of the ability to voluntarily suppress contextinappropriate behavior of reflexive acts is not fully developed until adulthood and this
process provides a context to examine the nature of obsessive-compulsive disorder in a
maturational context and within the framework of the basal ganglia and its networks.
The basal ganglia-thalamo-cortical circuits appear to play a modulating role in a wide range
of behaviors. At the cortical level, given convergence upon specified regions within the
frontal lobes, the behaviors in question would be those dependent upon the sensory-motor,
premotor, frontal eye fields, and dorsolateral and orbito-frontal outflow targets. Processes
such as the generation, maintenance, switching, and blending of motor, mental, or
emotional sets would be involved. In disorders that primarily affect basal ganglia function,
the planning and the execution of both motor and cognitive function within these behavioral
domains could be affected. As we have seen, there is a high degree of diversity and
complexity of activity within the basal ganglia. Despite the nature of the reverberating
circuits, consequences of disruption will depend upon the site of the lesion and the
associated interplay of neurochemical factors. For example, in the motor system, damage to
various striatal circuitry levels can result in either hypo- or hyperkinetic disorders of
movement. Following this analogy, it can be said that diverse lesions, depending on site, can
result in problems with the development and maintenance of behavioral sets
("hypophrenic") versus problems in relinquishing preferential sets ("hyperphrenic"). In
OCD, a "hyperphrenic" pattern would apply to those behaviors which are part of
obsessional rituals.
There is evidence of basal ganglia dysfunction from imaging studies of OCD, with both
reduced and increased volumes of caudate nuclei reported [57-59]. Increased caudate
metabolism has been found to be reduced after effective treatment of the OCD [60,61 and in
provoked or activated conditions, patients with OCD have shown increased caudate blood
flow [62. Such imaging studies point to the importance of orbito-frontal-basal gangliathalamocortical circuits in the pathogenesis of OCD. In autism stereotyped, ritualistic and
repetitive behaviors including compulsive rituals and difficulties in tolerating changes in
routine or environment, are characteristic. It has been suggested [24,63,64] that these
behaviors may share related pathophysiological mechanisms. Sears and colleagues [63]
analyzed with high resolution MRI the volume of the bilateral caudate, putamen, and
globus pallidus regions in a group with autism and a control group. No differences were
detected in volumes of the globus pallidus or the putamen. Significant enlargement of 8
percent of the total caudate volume was found in the subjects with autism. This greater
caudate volume was proportional to the increased total brain volume and enlargement of
other brain structures earlier reported in the patients with autism. [65].
Based on the aforementioned studies and the basis of this chapter, the cortico-basal ganglia
circuits linking the orbito-frontal and anterior cingulate cortex to the caudate nucleus might
account for the cardinal features of OCD. All of these structures have been implicated in the
evaluation of the significance of stimulating as positive or negative (rewarding or
punishing) and all, as we have seen, have been linked to aspects of executive function.
Cortical-basal ganglia circuits have been suggested to form a neuronal system critical for
habit learning and for the routine performance of habits, and structures of the OCD circuit
have specifically been implicated in the acquisition of stereotyped behaviors [66,67].
The basal ganglia are thought to exert control over action release through antagonistic
push-pull" output pathways, which serve to select intended actions [68]. As explained
earlier in the chapter, these functions are disrupted in hypokinetic disorders such as
Parkinson's disease, in which action is diminished, and in the hyperkinetic disorders such as
in Huntington's disease, in which action is excessive. Analogously, it has been suggested
that the function of these cortico-basal ganglia pathways may also occur in some
neuropsychiatric disorders including OCD and Tourette's syndrome.
Different sets of cortical-basal ganglia loops are thought to have specialized functions
depending on the cortical areas participating in the loops. This organization may account for
the symptom specificity of OCD as compared to other disorders of the basal ganglia and its
pathways. For example, in Tourette's syndrome, in which the characteristics of actions are
the predominant symptoms, the motor loop through the putamen is more effective than it
is in OCD according to neuroimaging data [69-71]. In OCD, which typically involves
obsessions as well as compulsive actions, the neuronal circuits interconnecting the orbitofrontal and anterior cingulate cortex with the basal ganglia are involved.
The caudate nucleus has been implicated in repetitive actions in monkeys. The orbitalfrontal and the anterior cingulate cortex both project to the ventral part of the caudate
nucleus and to the ventral striatum. In the monkey, these regions have been found to send
outputs not only to the pallidum, but also to a large part of the dopamine-containing
substantia nigra pars compacta, from which the nigro-striatal tract originates. The caudal
orbito-frontal and anterior cingulate/caudal medial cortex are also a major source of input to
the striosomal system in the head of the caudate nucleus. Striosomes in this region have
been linked to reward effects and may appear to be differentially active under conditions in
which the animals perform repetitive, stereotyped behaviors in response to dopamine
receptor agonists [72].
These features of the orbito-frontal and anterior cingulate cortical-basal ganglia circuits are
important not only for understanding OCD symptomatology, but also for understanding
the developmental aspects of these disorders. The basal ganglia may influence of motor
pattern generators in the brainstem as well as cognitive pattern generators" in the cerebral
cortex. The loops running from the neocortex to the basal ganglia and then to the thalamus
and back to the neocortex may help to establish cognitive habits, just as they may influence
the development of motor habits. If so, the cortical-basal ganglia loop dysfunction in OCD
could reflect both sides of basal ganglia function, motor and cognitive, to bring about
repetitive actions (compulsions) and repetitive thoughts (obsessions).
Alternatively, the basal ganglia may have as its task a process that takes input form cortical
and other sources and releases the output as chunks in order to sequence behavior,
important in forming coordinated, sequential motor actions and in developing streams of
thoughts and motivation, and perhaps playing the violin [63]. The architecture of corticalbasal ganglia circuitry could support the smooth progression from a cognitive framework
establishing priorities for potential behaviors to behavioral selection, thereby facilitating
fluid and adaptive behavioral output. Dysfunction of this cortical-basal ganglia system
could contribute to the symptoms of OCD. Individuals become stuck in a conceptual
framework, unable to shift from one priority set to the next, and thus remain locked into a
specific behavioral output program.
A large part of the frontal cortex receives inputs from the basal ganglia conveyed via the
thalamus. These same cortical regions not only project to the basal ganglia (mainly to the
striatum) but also to other regions including the thalamus. Cortical-thalamic loops are
critical for integrative and optimized cortical functioning. The adequacy of basal ganglia
function is necessary to facilitate associations among cortical inputs on the basis of context
and evaluative signals, and thereby promote behavioral automation, normally necessary to
reduce the information load on the system. The basal ganglia can relieve the frontal cortex of
the substantial computational load in carrying out executive functions. With both corticalthalamic and cortical-basal ganglia systems functioning under normal conditions, parallel
processing can occur with the cortical-thalamic circuits supporting conscious (explicit)
information processing and cortical-basal ganglia supporting automatic (implicit)
processing functions. If cortical-basal ganglia pathways functional abnormally, as in OCD
such parallel processing capabilities would be compromised. Information normally
processed automatically could intrude into the conscious domain of sessions, and
behavioral selection could become narrowed to compulsive acts. Such dysfunction could
contribute to the compelling nature of obsessions in OCD and to the stereotypic behaviors
carried out as compulsions.
The cortical-basal ganglia circuits appear dysfunctional in OCD, but the mechanisms are not
adequately understood at present. While we have seen that striatal lesions can induce
intense compulsive behaviors and stereotypies, we have not as yet found the existence of
subtle lesions of the striatum in OCD, perhaps as a result of the inadequacies of our current
measuring instruments. Magnetic resonance spectroscopy studies have suggested that there
exists reduced N-acetylaspartate levels within the striatum of persons with OCD, so that
neuronal density there may actually be reduced [17,74. Abnormal brain chemistry in OCD
could affect neurotransmission in cortical-basal ganglia circuits leading to the abnormal
metabolic activity seen in imaging studies indicated earlier. While little is known about
neurochemistry of OCD, the most successful pharmacologic therapy for OCD is treatment
with inhibitors of serotonin reuptake (SRIs) sites. Effective therapy with SRIs can reverse the
abnormal metabolic activity seen in OCD circuits, suggesting that the modulatory effects of
serotonin can act on the cortical-basal ganglia circuit defined in scanning studies [75].
Despite the clinical results, strong evidence of a primary serotonergic or other
neurotransmitter abnormality in OCD is still lacking. One suggestion is that SRIs have their
beneficial effects via downregulation of 5HT-1D autoreceptors within the orbito-frontal
cortex [75]. Even though neuroimaging studies have pointed to cortico-basal ganglia circuits
as being dysfunctional in OCD, it is still not clear what the functional abnormality is in the
circuits in OCD and how they contribute to the expression of OCD symptoms. Nor is it clear
how these circuits were normally, or help multiple loops of the system interconnecting
cortex, thalamus, and basal ganglia actually operate. Improvements in the temporal and
spatial resolution of imaging also now make it possible to follow the cascade of neuronal
activity changes that occur during the evolution of OCD symptoms. It should be possible in
the relatively near future to identify brain sites participating in the buildup of an obsession,
the attendant anxiety, the escalation of an urge, the performance of a compulsion, and the
resolution of the obsession and accompanying anxiety.
8. Basal ganglia in tourettes syndrome

Tourettes syndrome (TS) is a neurobehavioral disorder characterized by involuntary motor
and vocal tics beginning in childhood [76]. Approximately 50 percent of individuals with TS
also exhibit obsessivecompulsive disorder (OCD) in addition; tics and OCD individuals
demonstrate similar features and both are thought to arise from frontal-corticalbasal
gangliathalamocortical circuit dysfunction. Recent advances in understanding the
neurobiology of TS come from neuroimaging, post-mortem, and from physiological and
behavioral studies in human and non-human primates and rodents. These advances allow
us to understand the nature of the complex dynamics of the basal ganglia pathways and
how this disorder connects with other forms of cognitive dysfunction.
Tourettes syndrome is defined by motor and vocal tics that start during childhood, persist
for more than one year, and fluctuate in type, frequency and anatomical distribution over
time. A specific tic can be present for weeks, months or years and then suddenly cease.
Other tics emerge and disappear with no predictable time course. The motor patterns of tics
can involve individual muscles or small groups of muscles (simple tics), or more muscles
acting in a coordinated pattern to produce movements that can resemble purposeful
voluntary movements (complex tics). Many individuals with TS exhibit both simple and
complex tics. Simple tics include eye blinking, nose twitching, head jerking, eye deviation,
mouth opening, sniffing and throat clearing. Complex tics include head shaking, scratching,
touching, throwing, hitting, gestures or uttering phrases. There is a tendency for tics to
occur in bouts that wax and wane over hours, days, weeks or months [77].
OCD is strongly associated with TS both within individuals with TS and within families
[78]. As indicated above, OCD is characterized by repetitive thoughts that are involuntary,
senseless and often associated with anxiety, coupled with repetitive ritualistic behaviors that
are often performed in response to the premonitory thought or idea. There are striking
similarities between tics and OCD, and it is sometimes difficult to distinguish complex tics
from compulsions. Both tics and OCD include premonitory experiences such as sensations
(tics) or thoughts (OCD) that precede involuntary repetitive movements (tics) or behaviors
(OCD). Performance of the tic or compulsion typically terminates the premonitory
symptoms, at least temporarily.
Another feature common to both phenomena but important for placing OCD and Tourettes
within the cortico-basal ganglia loop process, is the impaired ability each disorder to inhibit
unwanted actions [79,80]. The spectrum of simple tics, complex tics, and compulsions
suggests that similar or shared pathophysiological mechanisms, but separate neural circuits,
might underlie these phenomena. These overlaps can be seen in cases of poisoning
especially with carbon monoxide in which the basal ganglia is selectively affected and
symptoms have been reported not dissimilar from those of Tourettes syndrome [79].
It is useful for us to examine cursorily issues related the neuropharmacology of TS to better
understand the nature of the loops and the connection of TS to OCD. Tics are suppressed
reliably by dopamine antagonists and OCD is improved by selective serotonin-reuptake
inhibitors (SSRIs) [81]. These facts implicate the dopaminergic and serotonergic pathways
and suggest the candidate loci for TS abnormalities. The implicated regions include the
striatum, the substantia nigra, and the prefrontal cortices. The dopaminergic complex of the
substantia nigra and ventral tegmental area and the serotonergic dorsal raph nuclei both
send major projections to the striatum. The striatum, prefrontal cortices and substantia
nigra are further interlinked by a web of pathways that form the corticalbasal ganglia
thalamocortical circuits [82-85].
We can infer from the literature cited previously that TS is a disorder of the basal ganglia
and its respective pathways in general, and a disorder of striatal organization and/or
function in particular. Some correlative data from other disorders supports the idea that
striatal dysfunction is involved in TS. Tics are seen also in disorders with known striatal
pathology, such as Huntingtons disease [21,76]. Abundant data implicates ventral striatal
dopaminergic neurotransmission in drug abuse and drug craving, attributes of which
overlap with obsessivecompulsive disorder (OCD) [86].
The clinical presentation of TS should reflect involvement of striatal function. Tics, in
general, are abnormal repetitive and stereotyped movements, but repetitive stereotyped
behaviors also occur normally. These behavioral effects are consistent with the effects of D1
receptor agonists on the response of medium spiny striatal neurons to stimulation [87]. D1
agonists tend to potentiate the current state of striatal neurons and reinforce ongoing
behaviors. The complex and perseverative behaviors caused by D1 agonists differ from the
effects of D2 receptor agonists, which tend to cause simple repetitive stereotyped
movements. Kelly and Berridge [86] suggest that super-stereotypy is analogous to complex
tics or OCD. Other stereotyped behavioral sequences are modulated by the basal ganglia
include complex defensive behaviors and facial movements.
Charles Darwin [88] had indicated that many facial movements are stereotyped among
mammals and important in non-verbal communication. Because tics commonly involve
involuntary head, neck and face movements, the importance of facial and related
movements in social communication might explain the disruptive nature of tics. There are
suggestions that regulation of socially relevant forms of communication is a
phylogenetically ancient function of the basal ganglia.
Additionally, the basal ganglia participate in brain circuits responsible for habit formation
and fixed action patterns [29]. Habits are physiological analogs of stereotyped,
unconsciously executed behavioral sequences such as tics, obsessions and compulsions. The
basal ganglia participate in circuits responsible for learning incremental stimulusresponse
associations epitomized by classical Pavlovian and instrumental conditioning [89]. Graybiel
has emphasized that the basal ganglia might combine or chunk individual stimulus
response associations into more complex behavioral sequences executed as stereotyped
units as we had seen earlier [68]. In addition, fMRI study of higher-order aversive
conditioning, in which key computational strategy that humans use to learn predictions
about pain was investigated. The investigators showed that neural activity in the ventral
striatum and the anterior insula display marked correspondence to the signals for sequential
learning predicted by temporal difference models. They identified the ventral striatum as a
key locus of such sequential learning [90]. Tics could represent a form of inappropriate habit
formation in which inappropriate stimulusresponse associations are formed. This
interpretation might correlate with the fluctuating nature and sensory component of tics.
In the study of non-human primates, electrophysiological studies of the intralaminar
thalamic nuclei have revealed that these nuclei influence striatal attentional mechanisms
and the processing of reward information [91]. These studies also suggest that intralaminar
thalamic nuclei encode information complementary to the reward prediction error
information provided by the dopaminergic nigrostriatal projection.
Basal ganglia circuitry models that we had described earlier in the paper view the normal,
tonically active inhibitory output of the basal ganglia as a brake on motor pattern
generators (MPGs) in the cerebral cortex and brainstem [92]. For a desired movement
controlled by a particular MPG, a specific set of striatal neurons is activated; these neurons
inhibit basal ganglia output neurons in the GPi and substantia nigra pars reticulata (SNr)
that project back, via the thalamus, to the cortical MPGs. The removal of tonic inhibition
from the GPi and SNr (the brake) enables the desired motor pattern to proceed. In parallel,
neurons in the subthalamic nucleus (STN) excite the surrounding majority of GPi and SNr
output neurons. These surround neurons project via the thalamus to competing MPGs,
increasing their inhibitory output and applying the brake to competing MPGs. The net
result is facilitation of intended movement with inhibition of competing movements. In the
generation of tics, it is hypothesized that an aberrant focus of striatal neurons becomes
inappropriately active, causing unwanted inhibition of a group of basal ganglia output
neurons, which in turn disinhibit an MPG leading to an involuntary movement. Repetitive
over-activity of a given specific set of striatal neurons would result in repeated, stereotyped,
unwanted movements [92]. Multiple tics would result from abnormal excessive activity of
multiple discrete sets of striatal neurons According to this hypothesis, each tic corresponds
to the activity of a discrete set of striatal neurons [79].
9. Basal ganglia in ADHD

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric
disorder estimated to affect six percent of school-age children [24]. It is manifested by
inattention, hyperactivity and impulsivity, which often respond substantially to treatment
with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in
cortico-striatal circuits, particularly those components modulated by dopamine and
therefore discussed in comparison with the other basal ganglia related disorders in the
paper. Teicher and colleagues [94] developed a functional magnetic resonance imaging
procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and
putamen) of boys 612 years of age in steady-state conditions. Boys with attentiondeficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen
bilaterally than healthy control subjects. Daily treatment with methylphenidate significantly
changed the T2 relaxation times in the putamen of children with attention deficit/
hyperactivity disorder. There was a similar but non-significant trend in the right caudate.
Teicher and colleagues concluded that attention-deficit/hyperactivity disorder symptoms
may be closely tied to functional abnormalities in the putamen, which is mainly involved in
the regulation of motor behavior.
Converging evidence implies the involvement of dopaminergic fronto-striatal circuitry in
ADHD. Anatomical imaging studies using MRI have demonstrated subtle reductions in
volume in regions of the basal ganglia and prefrontal cortex [e.g., 95]. Cognitive functioning
is mildly impaired in this disorder [for review, see 90]. In particular, cognitive control, the
ability to inhibit inappropriate thoughts and actions, is also affected and therefore we are
again dealing with a disorder of inhibition. Several studies have shown that this impairment
is related to the reduction in volume in fronto-striatal regions [96], and functional studies
have suggested that older children and adults with ADHD may activate these regions less
than controls during tasks that require cognitive control [e.g. 98, 99]. Durston et al. [100]
showed that the development of this ability is related to the maturation of ventral frontostriatal circuitry.
Volumetric abnormalities have also been associated with the basal ganglia and in turn with
attention deficit hyperactivity disorder (ADHD). Qiu and colleagues [101], to specify
localization of these abnormalities, employed large deformation diffeomorphic metric
mapping (LDDMM) to examine the effects of ADHD, sex, and their interaction on basal
ganglia shapes. The basal ganglia (caudate, putamen, globus pallidus) were manually
delineated on magnetic resonance imaging from typically developing children and children
with ADHD. LDDMM mappings from 35 typically developing children were used to
generate basal ganglia templates. These investigators found that boys with ADHD showed
significantly smaller basal ganglia volumes compared with typically developing boys, and
LDDMM revealed the groups remarkably differed in basal ganglia shapes. Volume
compression was seen bilaterally in the caudate head and body and anterior putamen as
well as in the left anterior globus pallidus and right ventral putamen. Volume expansion
was most pronounced in the posterior putamen. They concluded that the shape
compression pattern of basal ganglia in ADHD suggests an atypical brain development
involving multiple frontal-subcortical control loops, including circuits with premotor,
oculomotor, and prefrontal cortices.
Aron and colleagues [102] brilliantly outlined the nature of inhibition in fronto-basal-ganglia
networks relative to cognition. Their paper was not about the problems of ADHD
individuals per se but a thorough analysis of the neurophysiology of stopping. They hand
indicated that sensory information about a stop signal is relayed to the prefrontal cortex,
where the stopping command must be generated. They collected the evidence together
indicating that the right inferior frontal cortex (IFC) is a critical region for stop signal
response inhibition [103,104] with the most critical portion likely being the pars opercularis
(Brodmann area 44) in humans. The right IFC can send a stop command to intercept the Go
process via the basal ganglia (represented in Fig. 6b from Aron et al., [102]. The Go process
is likely generated by premotor areas that project via the direct pathway of the basal ganglia
(through striatum, pallidum, and thalamus), eventually exciting primary motor cortex and
generating cortico-spinal volleys to the relevant effector each interacting with the globus
pallidus [105]. The Stop process could activate the globus pallidus via a projection from the
subthalamic nucleus (STN). High resolution fMRI has shown activation of a midbrain
region, consistent with the STN, when subjects successfully stop their responses [105], and
diffusion tractography shows that this STN region is directly connected to the right IFC via a
white matter tract [102] (Fig. 6c). Thus, once the Stop command is generated in frontal
cortex, it could be rapidly conveyed to the basal ganglia via the so-called hyperdirect
pathway to intercept the Go process in the final stages of the race. Two recent studies
identified a third critical node for the stopping process in the dorso-medial frontal cortex,
including the pre-supplementary motor area) [106,107].
Figure 6. A, The interactive race model between Go and Stop processes [108]. The parameters were
estimated by fitting the model to thousands of behavioral trials from a monkey neurophysiology
study.B, Schematic of fronto-basal-ganglia circuitry for Going and Stopping. The Go process is
generated by premotor cortex, which excites striatum and inhibits globus pallidus, removing inhibition
from thalamus and exciting motor cortex (see text for details). The stopping process could be generated
by inferior frontal cortex leading to activation of the subthalamic nucleus, increasing broad excitation of
pallidum and inhibiting thalamocortical output, reducing activation in motor cortex. C, Diffusionweighted imaging reveals putative white matter tracts in the right hemisphere between the dorsomedial
preSMA, the ventrolateral PFC or IFC, and the putative region of the STN. Reproduced with permission
from Aron et al. [102]. D, Regions of the rat brain implicated in behavioral stopping. Stopping is
significantly impaired following excitotoxic lesions within the regions highlighted in red, whereas
lesions within the gray-colored regions have no effect on stopping. OF, Orbitofrontal cortex; IL,
infralimbic cortex; PL, prelimbic cortex; DM Str, dorsomedial striatum; NAC, nucleus accumbens (core);
DH, dorsal hippocampus; VH, ventral hippocampus; GPi, globus pallidus pars interna. (From Aron et
al. [102]),
10. Conclusions
Neural circuits linking activity in anatomically segregated populations of neurons in
subcortical structures and the neocortex throughout the human brain regulate complex
behaviors such as walking, talking, language comprehension and other cognitive functions
including those associated with frontal lobes. Many neocortical and subcortical regions
support the cortical-striatal-cortical circuits that confer various aspects of language ability,
for example. However, many of these structures also form part of the neural circuits
regulating other aspects of behavior. For example, the basal ganglia, which regulate motor
control, are also crucial elements in the circuits that confer human linguistic ability and
reasoning. The cerebellum, traditionally associated with motor control, is active in motor
learning. The basal ganglia are also key elements in reward-based learning. Data from
studies individuals with Tourettes syndrome, Obsessive-Compulsive Disorder as well as
with Broca's aphasia, Parkinson's disease, hypoxia, focal brain damage, and from
comparative studies of the brains and behavior of other species, demonstrate that the basal
ganglia sequence the discrete elements that constitute a complete motor act, syntactic
process, or thought process. Imaging studies of intact human subjects and
electrophysiologic and tracer studies of the brains and behavior of other species confirm
these findings. Dobzansky had stated, Nothing in biology makes sense except in the light
of evolution (cited in [108]). That applies with as much force to the human brain and the
neural bases of cognition as it does to the human foot or jaw. The converse follows: the mark
of evolution on the brains of human beings and other species provides insight into the
evolution of the brain bases of human language. The neural substrate that regulated motor
control in the common ancestor of apes and humans most likely was modified to enhance
cognitive and linguistic ability. Language and cognition played a central role in this process.
However, the process that ultimately resulted in the human brain may have started when
our earliest hominid ancestors began to walk.
Author details
Gerry Leisman
F.R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neurosciences, Garden
City, New York USA
The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel
Nazareth Academic Institute, Nazareth, Israel
Biomedical Engineering, Dept. Biomechanics, ORT-Braude College of Engineering, Carmiel, Israel
Robert Melillo
City, New York USA
The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel
Nazareth Academic Institute, Nazareth, Israel
Frederick R. Carrick
City, New York USA
Carrick Institute for Graduate Studies, Cape Canaveral, Florida USA
Department of Neurology, Life University, Marietta, Georgia USA
Acknowledgement
This work was supported by the Ministry of Science of the State of Israel, the F., R. Carrick
Research Institute, Inc., and Help the Hope Foundation.
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Chapter 2
Fetal and Environmental Basis for

the Cause of Parkinsons Disease
Clivel G. Charlton
http://dx.doi.org/10.5772/52680
1. Introduction
In Parkinsons disease (PD) dopamine producing neurons in the substantia nigra, pars
compacta of the midbrain and with their axons projecting to the neostriatum degenerate. PD
is classified as being familiar when it is known to be the result of genetic abnormalities, and
this represents about 5 to 10 percent of all cases. The other cases are idiopathic, represent 90
95 percent of all cases of PD and the causes are unknown. The expression of the specific
symptoms of idiopathic PD vary among individuals, and may be accompanied with other
brain disorders, including Alzheimers type dementia, depression and amyotrophic lateral
sclerosis (ALS). The common relationship among all of the degenerative disorders is that all
are caused by failure of specific functions that are under the control of identifiable neuronal
sets, with relatively low population number of larger neurons that usually occur in clusters
and with far reaching axons. These neurons are well represented by the nigrostriatal
dopamine neurons, and the degeneration of the neuronal set represents the major pathology
of PD. They are also represented by the basal nucleus of Meynert acetylcholine neurons with
major projections to the cerebral cortex that degenerate in Alzheimers disease (AD), and by
the upper and lower motor neurons with projections to the brainstem, spinal cord or motorend plate, that degenerate in ALS. These neuronal sets have specific prenatal and fetal
periods for their neurogenesis, migration and axonal extension during which they acquire
their specific phenotype that can be influenced by internally and externally derived
biochemical forces, including toxins and excesses and deficiency of regulatory factors that
will shape the physiological and functional destiny of these neuronal sets. If the influence is
of a positive or enhancing nature, the neuronal set will turn out to be functionally superior
or with exceptional resilience and longevity and will impart an enhanced character to the
individual. However, if the influence is deleterious it will cause harm to the neuronal set
and likewise will influence the character of the individual. For the latter, deficiencies may
occur at sub-threshold level, may continue in a subliminal and a graded way and may
2012 Charlton, licensee InTech. This is an open access chapter distributed under the terms of the
compromise resilience and functional longevity, finally serving as the weak link and
pairing with deteriorating changes that occur during aging to cause diseases, such as
Parkinsons disease. Whereas the gene has inherent command over the variation of
biological forms and some biological outcomes, it is the interacting entities derived from the
environment that really sway functional outcomes. Toxins, that may be endogenous or
exogenous, represent a set of these environmental factors and quite likely are responsible for
the cause of idiopathic PD and other degenerative disorders. So, this chapter will discuss the
idea, supported by experimental findings, that the substantia nigra dopamine neurons that
deteriorate to the point of causing idiopathic PD were impaired early in life at a subthreshold level. This occurs during the vulnerable stage of neurogenesis, neuronal
development and neuronal migration. The exposures of the substantia nigra dopamine
neurons to toxic or harmful influences early in life cause sub-threshold harm, and further
exposures to stress during aging cause additive insults that precipitate the symptoms of PD.
The early insults, the naturally low population of nigrostriatal neurons, the continuous
functional demands placed on the few nigrostriatal DA neurons and the far-reaching nature
of the axonal projections render the nigrostriatal DA neurons vulnerable. The high content
of cytoskeleton and their kinases seen as pathological markers for various degenerative
disorders (McGee and Steele, 2011) indicate that axonal damage to far-reaching neurons is a
preeminent occurrence in PD.
2. Major symptoms and the proposed causes for Parkinsons disease

The major clinical symptoms of Parkinsons disease (PD), an age-related disorder, are
resting tremors, hypokinesia, rigidity and postural instability (Tetriakoff, 1919: Foix and
Nicolesco, 1925) caused by the degeneration of the nigrostriatal (NS) dopaminergic pathway
and the depletion of dopamine (DA) (Greenfield and Bosanquet, 1953; Hornykiewicz, 1966).
The pathological features include extensive (about 70% or more) loss of dopaminergic
neurons in the pars compacta of the substantia nigra, the presence of inter-cytoplasmic
inclusions known as Lewys bodies and gliosis. It was reported also that norepinephrine
(NE) (Erhinger and Hornykiewicz, 1960) and serotonin (5-HT) Bernheimer et al., 1961) levels
are decreased and that acetylcholine neurotransmission (Yahr, 1968) is increased. A small
population of PD cases is caused by genetic abnormalities, involving alphasynuclein
(Polymeropoulos et al, 1997; Papadimitrior et al, 1999 and Kruger et al,1998, Dauer et al,
2002), ubiquitin (Leroy et al, 1998) and apolipoprotein E (APOE), (Kruger et al, 1999).
Changes in chromosome 2p13 (Gasser et al, 1998), cyp2D6 (Kruger et al, 1999; Christensen
et al, 1998; Kosel et al, 1996; Bon et al, 1999, Sabbagh et al, 1999) as well as mitochondria
tRNA (A4336G) (Epensperger et al, 1997) have also been reported. The mutation of the
parkin gene is closely associated with juvenile PD (Kitada et al, 1998), which has about eight
variants (Lansbury and Brice, 2002). It should be noted however, that multiple other PD
cases have been screened and they did not harbor mutations (Giasson et al, 2000), but gene
mutations may serve as vulnerable markers, superimposed by environmental factors and
age-related wear-andtear. The root-cause of idiopathic PD is unknown, but various factors
are implicated, including the oxidation of dopamine, free radical-mediated oxidative injury,
Fetal and Environmental Basis for the Cause of Parkinsons Disease 33
mitochondrial abnormalities, excitotoxins, over exposure to manganese (Chu et al, 1995;

Hochberg et al, 1996) and carbon monoxide, the intake of beta-methylaminoalanine
(Spencer, 1987), benzyl-tetra-hydroisoquinolines and tetra-hydroprotoberines (CaparrosLefebvre and Steele, 2005), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Davis et al, 1979),
methanol (Guggenheim et al, 1971). As well as the potent methylating agent,
methylazoxymethanol (Ince and Codd, 2005) and excess methylation via high utilization of
the endogenous S-adenosyl-L- methionine in the brain (Charlton and Way, 1978; Charlton et
al, 1992; Charlton and Mack, 1994).
2.1. Aberrations in non-basal ganglia systems

In PD the basal ganglia is the primary affected structure, but lesions have been identified in
the locus ceruleus (Selby, 1968; Alvord et al, 1974), the hypothalamus (Jagar and Bethlem,
1969; Ohama and Ikuta, 1976; Langston and Forno, 1978), the dorsal motor nucleus of vagus
(Eadie, 1963; Vanderhaegen et al 1970), the sympathetic ganglia (Jagar and Bethlem, 1960;
Vanderhaeghen et al., 1970; Rajput and Rozdilsky, 1970 and Forno and Norvill, 1976) and in
the adrenal medulla (Jager, 1969) as well. Furthermore, Lewys bodies, the standard marker
for PD, have been seen in the cerebral cortex, anterior thalamus, hypothalamus, amygdala,
basal forebrain, dorsal motor nucleus of vagus, adrenal medulla and locus ceruleus. The
clearly un-circumscribed localization of lesions in the patients or victims of PD means that
the changes or the incidents that cause the dopaminergic cell loss in the nigrostriatal system
may not specifically target the basal ganglia, but instead the nigrostriatal dopaminergic
neurons may be more vulnerable or sensitive. In other words, the factors that are involved
in the cause of, at least, some cases of PD may also cause harm to other cell populations, but
the basal ganglia neurons are more vulnerable and will die when other neuronal sets remain
alive and function normally. This means that a state of vulnerability or sensitization may
exists for PD and that the occurrence of damage to other neuronal pool may help to explain
the variation in the expression of the PD syndrome.
3. The fetal basis hypothesis for Parkinsons disease

PD is age-related but a large percentage of the older population does not suffer from the
disorder, although aging is accompanied with pronounced and progressing reduction in
motor and other functions. The age-dependent increase in the frequency of essential tremor
(Elble 1995; Koller and Huber, 1989), the occurrence of kyphotic posture, diminished arm
swing, shorter strides (Murray et al, 1969; Elble et al, 1992; Elble et al, 1991, bradykinesia
(Waite et al, 1996) and slowed reaction time (Weiss 1965; Welford, 1977) are signs found to
be associated with aging, but the abnormalities are distinguishable from the changes that
occur in PD. This suggests that, during normal aging and as a rule, the nigrostriatal DA
neurons do not deteriorate to the point of causing PD. Therefore, it is very possible that for
PD symptoms to be expressed in the aged, some primary changes that render the
nigrostriatal DA neurons vulnerable occur during the earlier life of the PD patients and
serve as the underpinning for the deleterious age-related changes that normally occur. So,
the functional age-related changes pair with the early predispositions to precipitate the
symptoms of PD. Furthermore, there is the high probability that the causes of the
vulnerability that occur early in life are based on chance and occur during a critical period
when nigrostriatal dopamine neurons are structurally responsive to endogenous and
exogenous toxic type of interventions.
3.1. Chance encounter of the nigrostriatal neurons with harmful factors

It is proposed that chance encounter of factors with the NS DA neurons at critical times
during their development eventually shape the long-term outcome of the neuronal pool. If
the encounter decreases the longevity of the neurons idiopathic PD will occur. This will
underlie the sporadic feature of idiopathic PD, and the nature of the early encounter will
determine the pathological characteristics. So, the cluster of PD cases caused by the outbreak
of the epidemic encephalitis lethargic in 1919 that killed about one million people
worldwide and left millions more frozen with the symptoms of PD and which decline
rapidly after 1925 (Ravenholt et al, 1982) represent a special but a typical set of
parkinsonism. The Guam Parkinsons dementia complex (PDC)-amyotrophic lateral
sclerosis (ALS) syndrome proposed to be caused by the toxins contained in flour prepared
from the cycad plant (Spencer et al, 1987) suggests a syndrome that is caused by longterm
exposures that target the nigrostriatal neurons, motor neurons and basal nucleus of Meynert
acetlycholinergic neurons. In these cases the diversity in the character of the syndrome is a
reflection of the neuronal sets that were harmed. So, the individuals that develop idiopathic
Parkinson's disease, and likely other neurodegenerative disorders, were marked early in life
for the disorder. The early process may be synonymous to natural selection that occurs by
chance, and helps to define the variation of phenotypes among a population. In the case of
PD, the variation may be defined by the magnitude of the reduction in the number of
nigrostriatal dopaminergic neurons, and/or deficiencies in the metabolic capability or
resilience of the neurons. Therefore, the nigrostriatal DA neurons of the PD patients may
have experienced early exposure to environmental, nutritional and/or metabolic toxic
interventions. This early exposures may result in DA neurons that lack the reserve capacity
to survive during the natural life of the individual, but they function at a level of output that
is above the threshold at which the symptoms of PD occur (pre-threshold). During the
progression of time or during aging, however, subtle but accumulative changes occur that
further damage the nigrostriatal DA neurons and the additive effects precipitate PD-like
symptoms. Thus, the fetal basis hypothesis proposes that by chance early interventions
render the nigrostriatal neurons sensitive, susceptible or vulnerable, characteristics that
enable changes involving the wear-and-tear of living or the exposure to toxins or
traumatic events later in life to take a toll on the vulnerable NS neurons and cause PD.
3.2. High workload may explain the vulnerability of the nigrostriatal neurons
The normal population of nigrostriatal pigmented neurons is relatively low, showing a
mean value of 163,238 42,372 in normal human (Ma et al, 1997). The relatively low
population number of the nigrostriatal neurons and the high workload placed on these
specialized cells play a role in their metabolic durability. This relationship may help to
explain the rapid decline in the ability to effectively execute rapid and skillful movementrelated skills as a function of aging. This is evident in the short time that a competitive
athlete can maintain his or her exceptional ability. A 100-meter runner, for example, is
normally competitive for only one or two olympic game and skillful ballet dancers are
young people. Even the ability to play the game of golf requires skills that deteriorate to
non-competitiveness by the time the athlete reaches early middle age. So, even under
normal living condition the nigrostriatal neurons are under moment-by-moment demands
by the motor and other functions that they control, and their capability naturally
deteriorates in time. The demands placed on these neurons by muscles, for example, are
continuously occurring, even during sleep, since skeletal muscle activities are maintained
for limb and eye movements. Demands on the nigrostriatal neurons are continuous during
regular activities and increased during stress-related physical activities, so, these neurons
never rest, unlike neurons that control functions such as hearing, vision and cognition that
are at rest at least during sleep. Therefore, while other neuronal sets with less stressful
functions and without experiencing an early assault will age at a regular rate, the functional
stress imposed on already susceptible dopamine neurons, during the process of living, will
cause them to deteriorate at a fast rate to below the threshold that maintains normal
functions. This means, therefore, that the prenatal exposure hypothesis will explain cases of
juvenile PD that occur at about the age of forty years, in patients that are functionally
normal high into the thirties. So, early markers for juvenile PD that are known to be caused
by genetic abnormalities, likely exist long before the occurrence of the PD symptoms. The
early markers may exist as subtle but serious sub-threshold genetic nigrostriatal
abnormality that is below the threshold at which PD symptoms are expressed. So, as
compared to idiopathic PD, that has its onset about in the sixth decade, juvenile PD, because
of it more serious early impairments, requires a shorter duration of time before the added
stress induces threshold level nigrostriatal damage. The overall analogy, therefore, means
that at least two stages or two sets of factors or groups of factors are involved in PD:
1.
2.
The first stage: the predisposing/sensitization/susceptible/vulnerable stage.

The second stage: the inducing/precipitating/superimposing stage.
Again, the first stage is defined by subtle or sub-threshold level of adverse changes that start
early in life and form the weak link for the second stage, defined by stressful events
occurring later in life and coupled with the first stage to cause the expression of the disease
symptoms. It should be noted that normal functional and age-related existence may cause
enough stress to produce the added-on second stage damage to the nigrostriatal neurons in
individuals with early stage predisposition.
4. The predisposing, sensitization, susceptible or vulnerable stage of the

hypothesis
Normally, immature neurons or neuroblast are subject to chemical and mechanical
influences that cause them to migrate to various locations in the nervous system, to extend
axonal and dendritic processes toward other cells and then to make and break synaptic
connections with these cells before a final pattern of branching and connections are
established (Levitan and Kaczmarek, 2002). Moreover, factors released by other cells
influence the type of neurotransmitter the neuron will synthesize and the specific type and
mixture of receptor, ion channels and other proteins that determine the characteristics of the
fully differentiated neurons (Levitan and Kaczmarek, 2002). Along with or besides the
normal pattern of development that occur, the differentiating and young neurons may be
subjected to toxic and interfering influences that shape them for life. There could be failure
in the normal process of apoptosis, that acts via cytochrome c, caspase 9, caspase 3 and other
cellular constituents, to cause cellular pruning and to allow the remaining neurons to
survive and to be properly organized.
In general, brain neurons are known to be susceptible or vulnerable to insults during
prenatal and the early postnatal stage of the life of the individual. This is the basic reasons
for the practice of protecting the pregnant mother, new born and young children from
chemical and other potentially harmful exposures. For the midbrain dopaminergic system,
the most susceptible time is likely to be the period of neurogenesis, proliferation and
migration of the cells to produce the nigrostriatal dopaminergic phenotype. These midbrain
dopamine neurons are generated early during development, first in the midbrain-hindbrain
junction (Voorn et al, 1988), and they migrated radially to their final position in the ventral
midbrain to form the substantia nigra, the ventral tegmental area and the retrorubal nuclei
(Perrone-Capano and di Porzio 1996). Tyrosine hydroxylase (TH) immunoreactivity is used
to identify those dopamine tegmental neurons, and the first appearance of the TH marker is
regarded as the birth of the tegmental cells, which occurs on embryonic day 9 for the mouse.
The periods close to the birth of these neurons are likely to be a very critical window
through which the environment causes long-term changes to the cells and to the motor
performance of the organism. In fact, it is these types of manipulations that may be relevant
in causing diseases and in enhancing special features related to the functions of the basal
ganglia, and they will have effects similar to natural selection and imprinting.
The signal for the differentiation of the NS DA neurons is through a protein called the sonic
hedgehog (SHH). The amino-terminal product is the inductive moiety. SHH is produced by
the floor plate cells and induces the dopaminergic phenotype (Hayes, et al., 1995). The signal
for the SHH protein can be antagonized by increasing the activity of cyclic AMP-dependent
protein kinase A. High activity of cAMP blocked the induction of dopamine neurons (Hayes
et al, 1995), therefore it could be reasoned that other molecules, e.g. environmental toxins,
that modulate cyclic AMP-dependent protein kinase A will interfere with cellular
differentiation and migration of these emerging DA neurons. Biomolecules may also affect
the metabolic and structural components of the emerging DA neurons, resulting in different
degrees of effects that may be enhancing or detrimental to the functions and longevity of the
new born DA neurons. If the modulation enhances the metabolism and functions of the
nigrostriatal neurons it is expected that the adult may possess motor features that are
superior in functions, and will endure to advance ages. On the other hand if the
modulations impair metabolism and functions of the nigrostriatal neurons, it is expected
that the adult will possess motor features that fail early in life to produce PD symptoms. So,
the severity of the prenatal impairment will dictate the age of onset of PD symptoms.
Susceptible type of impairments that are most severe, and do not result in death of the fetus,
will be closest to the threshold at which PD symptoms are seen, so patients with early onset
or juvenile PD may be endowed with sub-threshold but severely impaired NS system that
developed early in life.
In summary, the period for the reorganization of the cellular membranes, organization of
the chromatid for cell division, the synthesis of structural proteins, production of subsystems for neurotransmitter synthesis and storage and the synthesis of molecules for
intracellular transport and cell movement make the emerging dopaminergic cells well
exposed to interfering factors and incidents. During this transforming cellular period the
lack of essential metabolites, exposure to inappropriate metabolites and to exogenous and/or
endogenous toxins can interfere with the molecular processes to cause permanent changes
to the differentiating and migrating cells, that will reduce the resilience of the cell
population. The affected neuronal set will become sensitive, susceptible, predisposed or
vulnerable to the wear-and-tear of living or to toxic type of interventions that are
encountered later in life. So, harmful basal ganglia neuronal changes that occur early in life
could set the stage and shape the destiny of the individuals to the development of PD.
The dopamine neurons that are degenerated in PD have as their distinguishing feature long
axons that project from the substantia nigra in the midbrain to the neostriatum in the
forebrain region. One of the key sub-structures of the axon is cytoskeleton. Since they are
involved in major cytoarchitectural changes during the development of the nigrostriatal
dopamine neurons, the cytoskeleton and other associated molecules, including the kinases,
are prime targets for modifications that will determine the outcome of the nigrostriatal
dopaminergic neurons.
4.1. The involvement of cytoskeleton and alpha-synuclein as axonal constituents

The cytoskeleton proteins are important structures in the developmental and maintenance
of the basal ganglia dopaminergic neurons. They support cellular shape, axonal and
dendritic extensions, trafficking and transportation of macromolecules. More importantly,
they allow the neurons to extend their reaches and influences far distances from the soma in
the midbrain to the striatum in the forebrain region. So, the cytoskeleton serves to
distinguish the new nigrostriatal dopaminergic neurons from the parent parochial cells and
is the key components that enable the neurons to be functional; noting that the cell bodies
may be correctly in place in the substantia nigra, but they will be non-functional without
their far-reaching axons. So, by virtue of their relative cyto-architectural and functional
significance, cytoskeleton synthesis and assembling ought to be one of the most vulnerable
features affected by agents that interfere with the differentiation and proliferation of the farreaching nigrostriatal dopaminergic neurons. Accordingly the molecules of the cytoskeleton
protein classes, (i) microtubules, (ii) neurofilaments and (iii) microfilaments are seen as
prime targets. Their vulnerability may help to explain why key markers of
neurodegenerative disorders are mostly insoluble remnants of cytoskeleton protein. Lewy
bodies, the major pathological marker for PD are composed principally of neurofilament
proteins, alpha synuclein, actin-like protein, microtubules associated protein 2 (MAT 2),
microtubules associated protein 5 (MAT 5), syaptophysin, tubulin (Giasson et al, 2000).
Lewy bodies are also reactive for cytoskeletal protein kinases, calcium/calmodulindependent protein kinase (Iwatsubo et al, 1991), cyclin-dependent kinase 5 (Nakamura et al,
1997) and stress activated protein kinases (Giasson et al, 2000).
The microtubules include the subunits, (i) alpha-tubulin and beta-tubulin and (ii)
polymerization regulator proteins that include microtubule associated protein 2 and 5
(MAP2 and MAP5). Microtubules span the length of axon and dendrites, serving as the
track for macromolecular transport. They are the major component of mitotic spindle, an
organelle that participates in cell division and are of importance in the differentiation of cells
to form the nigrostriatal dopaminergic neuronal phenotype. Microtubules also play an
important role in cell movement. The subunit, tubulin, synthesized in the cell body is
actively transported down the axon, so they are relatively easy target for interfering
molecules, such as colchicines. Moreover, the turnover of microtubules requires the
polymerization and depolymerization of the molecule. This is a cyclic process that is more
stable in mature dendrites and axons but is active in dividing cells, which again is a
potential target for molecules, such as colchicines and vinblastine. So, the process that
involves polymerization and depolymerization of microtubules is a weak link in the life of a
far-reaching neuron during which modifications of a permanent nature can be made.
The neurofilaments are the most abundant fibrillar components of axon (Schwartz, 1991).
They include the light (L), medium (M) and heavy (H) molecular weight neurofilament
subunit proteins. Neurofilaments are oriented along the length of the axons, are most
abundant in axons and are critical for axonal extension, a feature that enables the DA cell
bodies in the substantia nigra to extend their axons to the striatum. So, neurofilament
proteins form the backbones of the nigrostriatal DA neurons and interference with the
protein will likely cause significant and permanent change.
Microfilaments are made up of globular subunits of (i) beta-actin and (ii) gamma-actin.
Actin plays a major role in the function of growth cones and in dendritic spines. High
concentrations occur in dendritic spines and they are located just underneath the
plasmalemma, together with a large number of actin binding proteins, including spectrinfodrin, ankyrin, talin and actinin. They play key role in motility of growth cone during
development, the generation of specialized micro domains on the cell surface and in the
formation of presynaptic and postsynaptic morphological specializations. They undergo
cycles of polymerization and depolymerization (Kandel, Schwartz and Jessel, 2000).
Alpha-synuclein is also a likely prime target for prenatal toxins. It is a heat stable protein
associated with synaptic vesicles and axonal terminals (Withers et al, 1997). It plays
important roles in neurotransmission, synaptic organization and neuronal plasticity (George
et al, 1995). Alpha-Synuclein is the major building block for the fibrillary component of
Lewys bodies (Pollannen et al, 1993), the major antigenic component of Lewys bodies
(Baba et al. 1997; Spillantini et al, 1997) and may be critical for the expression of PD
symptoms (van Duinen et al, 1999). It is also a component of the thread-like structures seen
in the perikarya of some neurons in the brainstem nuclei of the PD victims (Arima at al,
1998). It has been shown also that the association of alpha-synuclein with membrane
promotes alpha synuclein aggregation (Lee et al. 2002) and that alpha-synuclein binds with
dopamine transporters (Lee et al. 2001).
The interaction of the cytoskeleton proteins and other proteins of interest has been observed.
For example, tubulin seeds the fibrillar form of alpha synuclein (Alim et al, 2002) and parkin
has been shown to be a novel tubulin binding protein (Ren et al, 2003). It was also observed
that 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of MPTP, reduced the
synthesis of tubulin in PC12 cell model (Capelletti et al, 1999, Capelletti et al, 2000) and that
MPP+ inhibited tubulin polymerization (Capelletti et al, 2001), by specifically binding to
tubulin in the microtubule lattice (Capelletti et al, 2005). Antibodies that recognize
phosphorylated neurofilamant-M and neurofilaments-H also label Lewys bodies, therefore
the phosphorylation state of neurofilaments may be important in the formation of Lewys
bodies (Julien and Mushynski, 1998; Sternberger et al. 1983; Lee et al. 1987).
4.2. There may be a window of vulnerability for nigrostriatal dopamine

neuronal sensitization
PD occurs in a relatively small number of the population, which may be so because a
relatively short window of time exists during which the nigrostriatal DA neurons of the
individual can be easily harmed. Such a window of vulnerability, we believe, is the period
of differentiation, neurogenesis and migration of cells to form the nigrostriatal DA neurons,
and this period occurs during gestational day 9-11 in mice. As mentioned above, the
synthesis and laying down of cytoskeleton and neurotransmitter synthesis, storage, uptake
and release capacities are likely the prime time during which the transforming cells are most
vulnerable to toxic type of interference and inappropriate levels of metabolites and factors.
So, idiopathic PD and some other degenerative disorders may have their origin in the fetus
and the vulnerability may occur during pregnancy. This should not be seen as shifting the
blame of having PD on pregnancy, but the fact is, pregnancy also produces the life and
existence of the individual in the first place. So, the probability of having PD would be
proportionate to the duration of the neurogenesis/neuronal development time, the number
of pregnancy, the frequency by the individual encounter the toxic factor and the potency of
the toxic encounter.
4.3. The susceptible stage may set the age of onset of PD and the severity of PD
symptoms
If the rate of change is constant during the precipitating stage, it means that the more severe
the sensitization, susceptible or vulnerable stage of affliction is, the earlier will the threshold
reached for expressing the symptoms of PD. Thus, the age at which PD occurs may be
directly related to the severity of the impairments that occur during the sensitization or the
first stage affliction. So, juvenile PD may be marked by basal ganglia that were severely
affected or were made less resilience by the changes that occur during the sensitization,
susceptible or vulnerable stage of affliction. The individuas whose basal ganglia are less
severely affected during the sensitization, susceptible or vulnerable stage may experience a
delay in the expression of PD symptoms, since more harm will need to be made during the
precipitating stage to reach the threshold at which PD symptoms will be seen. So
individuals with the least affected nigrostriatal system during the susceptible stage are those
that may live without the experiencing the symptoms of PD. In other words, the severity of
the changes that occur during the sensitization, susceptible or vulnerable stage may very
well predetermine the age at which PD symptoms will occur and the severity of the
symptoms.
4.4. The number of NS DA neurons may also determine the susceptibility to PD

The proposed early exposures of the basal ganglia may reduce the number of NS neurons in
a random pattern, among the population, so that the average individual possesses a normal
population of, say 120,000 (120K) NS DA neurons and with various fractions of the
population having values above and below the 120K. Thus, a bell-shaped frequency
distribution pattern will exist, with some individuals represented at the far left of the curve,
say with 30K or 25%. The individuals among the population who will most likely develop
PD would be those endowed with a low (pre-threshold) population of 30K NS DA neuronal
subset and PD will occur following a reduction of merely 6K neurons, to 20% of the mean.
This low population number of neurons, similar to the marginally resilience neurons
mentioned above, would constitute the 1st stage or the sensitization, susceptible or
vulnerable stage, and contributes to the cause of PD. During the wear-and-tear of aging, that
involves the reduction of NS DA neurons, individuals with the 30K number of NS DA
neurons will be those most likely to develop PD symptoms and also at an early age
(juvenile). This analogy could form the basis for the early-onset to late-onset PD cases. It
may also explain the PD-like dispositions that are exhibited by the very old, due to the
chronic reduction of NS DA neurons. The population at the right of the bell shape curve
may be those that live to old ages without basal ganglia impairments.
4.5. The coincidental involvement of other neuronal sets with the NS neuronal
changes
When the NS DA neurons are made susceptible during the early stage of life other neuronal
groups may also be harmed by the modifying factor(s) and the coincidence will determine
the occurrence of other symptoms with the symptoms of PD. The coincidental involvement
may occur if the window of exposure or neurogenesis for the basal ganglia DA neurons
overlap the period of neurogenesis for other neuronal sets, or the period of exposure to the
interfering factor/factors is long enough to overlap the period of neurogenesis of all
neuronal sets. If that is the case all the neuronal sets will be harmed by the interfering
factor/factors. For example, if the nucleus basilis of Meynert acetylcholinergic neurons and
the mesolimbic or mesocortical catecholaminergic neurons are affected, as proposed for the
NS DA neurons, these other neuronal sets will be scared early in life and succumb to the
wear-and-tear of aging later in life. Such co-incident may explain the comorbidity of
Alzheimer-like dementia as well as depression with the occurrence of PD. It is of interest,

therefore, that the Guam amyotrophic lateral sclerosis-parkinsonism-dementia that may be
caused by toxins from the cycad plant (Spencer, 1987), may involve the early damage to
upper motor and lower neurons, NS DA neurons and nucleus basalis of Meynert neurons
and that the failure of the neuronal sets later in life precipitates the triage of symptoms. This
may involve a longer time for the early exposure, which is reasonable because the toxin in
cycad was taken in as food. So, the impairments of various neuronal sets during the stage of
neurogenesis and neuronal development may help to explain the variations and complexity
of the PD related syndrome.
4.6. Agents that may cause neuronal susceptibility

Parkinsons disease was described by James Parkinson in 1817, almost two centuries ago. So,
if external factors are involved in the cause of PD they were in the environment during those
early times and the factors would be widely distributed since the occurrence of idiopathic
PD is universal. Moreover, since aging is the key risk factor for having PD, PD can be seen
as the outcome of the changes that occur during the wear-and-tear of aging. As mentioned
above, the best scenario is that the changes in aging coupled with early events that render
the nigrostriatal neurons susceptible. Several agents or conditions may be involved in
causing the NS DA neurons to be susceptible because all that is required is for the factor to
cause damage to dividing and developing neurons, and for the factors to be available during
the critical stage of the birth of the NS DA neuronal phenotype. The deficiency and excesses
of otherwise normal metabolites, such as momentary fetal hypoxia during the development
of the NS DA neurons may be all that is required to trigger the sensitization, susceptible or
vulnerable stage. There may also be excesses of normal metabolites, since high activity of
cyclic AMP can block the induction of dopamine neurons (Hayes et al, 1995).
It is highly likely that the susceptible phase occurs over a short period, which may help to
explain the relatively low incidence of PD. We have used the toxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), to model the sensitization stage in the mice (Muthian et
al, 2010), so structurally similar agents to MPTP that occur in nature could affect the basal
ganglia long before the synthetic MPTP became available as a toxicant. It is proposed, also,
that agents such as colchicine and vincristine that have been in use as medicine for over 2000
years could have played a role as a sensitization factor for PD. Colchicine is an alkaloid from
the Lily family, including Autumn lily or Colchicum autumnale and of the saffron family,
that is still used today, as food coloring and cosmetics. Vincristine is an alkaloid obtained
from the periwinkle plant. These two compounds are not known to target the nigrostriatal
dopamine neurons, however, they bind to tubulin and prevent the polymerization of
tubulin to form microtubules. By doing so, they interfere with cell division and are known
to arrest cell division in the metaphase stage. It means that these agents will interfere with
the division of the newly proliferating nigrostriatal dopamine neurons if they are
administered during the period of neurogenesis. They will also interfere with cellular
transport, cell polarization, cell growth and axonal extension that depend on the integrity of
cytoskeleton proteins. These features are especially important for a group of cells, such as
the basal ganglia DA neurons that require their long axonal reaches to the striatum for their
actions and effectiveness. By interfering with the assembling of the microtubules of the cells,
colchicines and vincristine and now MPTP, via MPP+, (Capelletti et al, 2005), will also
impede and/or retard the new neurons from migrating to their place of destination in the
substantia nigra, pars compacta. The phenomenon will also prevent the cells from extending
their axons to their targets in the striatum. Since colchicines have been found to abolish
retrograde transport in neurons resulting in the withdrawal of presynaptic terminals
(Schwartz, 1991), these alkaloids will eventually result in cell death due to the lack of contact
or contact inhibition. Today colchicines are used as a research tool and as a drug and the
range of their toxicity is well known. Toxins, such as colchicines and vincristine are not
disease specific, but they can cause a specific disease outcome based on the timing of their
toxic effects to coincide with the vulnerable stage of a cellular substrate that underlie a
specific disorder. For example, if a fetus is exposed to colchicines or vinblastine during the
period of the neurogenesis and development of cells to produce the nigrostriatal
dopaminergic phenotype, these neurons will be selectively harmed, and likely will result in
PD later in life. If the effect of the toxin coincides with the birth of the nucleus basalis of
Meynert neurons, Alzheimers type dementia will occur. However, if the exposure time is
extended to overlap both the birth of the nigrostriatal and acetylcholine neuronal sets the
final symptoms will show parkinsonism and Alzheimers like dementia.
4.7. Testing the prenatal sensitization, susceptibility or vulnerable concept

In studies designed to test the effects of toxin on the development of the midbrain neurons
that are destined to become the nigrostriatal phenotype, we administered MPTP during the
stage of neurogenesis, proliferation, migration and development of these DA cells. In the
mouse, this period occurs during gestation day 9 - 11 and is marked by the appearance and
maturation of TH-containing immunoreactive nigrostriatal neurons. The pregnant dams
were treated with various dosages of MPTP or with phosphate buffered saline (PBS), as the
control. We found that the dams treated with the 20 mg/kg and 30 mg/kg levels of MPTP,
amounts that did not caused marked acute toxicity in the dams, caused very low to no full
term pregnancy, suggesting that the higher dosage of MPTP may cause the pups to be
aborted. For the 10 mg/kg of MPTP, however, the dams delivered normal looking pups, and
this dosage was used to test the prenatal effects of MPTP.
4.7.1. Prenatal effects of MPTP on body weight, motor activity, TH and DA.
The outcome showed that the birth weights of pups born to dam that were exposed to
prenatal 10 mg/kg of MPTP lagged behind the PBS control, but caught up within 4 weeks
(Muthian et al, 2010). This recovery in birth weight and the appearance of the offspring
indicated that they were in good physical health. The prenatal exposure to MPTP also
reduced motor activity, measured as the total distance travelled, the movement time and the
number of movements (Muthian et al, 2010) and Western blot detection showed that the
exposure of the pregnant dams to MPTP at G9-11, that targeted the developing nigrostriatal
dopamine neurons, reduced striatal tyrosine hydroxylase (TH) protein by 38%. DA and the
metabolites of DA were also studied in the brain of the 12 week old C57BL/CJ mouse
offspring following the prenatal exposure to10 mg/kg of MPTP or to PBS (Muthian et al,
2010). As shown in table 1, the prenatal exposure to MPTP reduced the concentrations of
striatal dopamine (DA), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) by
13.80%, 16.48% and 66.25%, respectively (Muthian et al, 2010). The level of
dihydroxyphenylacetic acid (DOPAC) showed a slight increase (table 1).
Dopamine and metabolites (ng/mg protein)
Prenatal
Treatments
PBS
MPTP
DA
[%]
157.3 17.30
[0.0]
135.6 4.80
[13.8]
DOPAC
[%]
5.2 0.76
[0.0]
5.9 .88
[+13.46]
HVA
[%]
18.2 0.80
[0.0]
15.2 0.80
[16.48]
3-MT
[%]
1.60 0.20
[0.0]
0.54 0.12
[66.25]
Table 1. Effects of prenatal MPTP on striatial DA, DOPAC, HVA and 3-MT. C57BL/6J dams were
treated with 10 mg/kg MPTP or with PBS during G8-G12 to target the developing nigrostriatal
dopamine neurons in the fetus. The table shows the levels of DA, DOPAC, HVA and 3-MT in the
striatum of the 12 weeks old offspring. MPTP reduced DA, HVA and 3-MT, as compared to the values
for the PBS group.
PBS
MPTP
Figure 1. Substantia nigra, compacta of mice showing tyrosine hydroxylase immunoreactivity. The
figure shows tyrosine hydroxylase (TH) immunoreactivity (I) in the substantia nigra compacta of a 12
weeks old mouse that was exposed to PBS (left) and one that was exposed to MPTP (right) in utero. The
pregnant dam was treated during gestation days 8-12 and TH-I was determined in the 12 weeks old
offspring.
Figure 2. Nissl staining of the substantia nigra of mice exposed to prenatal PBS or MPTP. The Nissl
staining highlights the cells (dots) of the substantia nigra, pars compacta. The overall morphology is
closely similar, but the cellular composition of the PBS exposed mice are more concentrated within a
defined zone in the compacta and with larger cells, as compared to the mice exposed to MPTP in which
the smaller cells, especially within the rostro-medial (R-M) zone, are more abundant.
4.7.2. Prenatal MPTP on the in situ TH immunoreactivity in the substantia nigra

Figure 1 shows the effects of the prenatal exposure to MPTP on midbrain TH
immunohistochemistry. Polyclonal antibodies against tyrosine hydroxylase (TH) were used
to detect the changes that occurred in 12 weeks old mice offspring that were exposed to 10
mg/kg of MPTP, in utero, during G8-12 of the dams pregnancy, when the midbrain neurons
are developing the tyrosine hydroxylase phenotype. The results show that TH-like
immunoreactivity was reduced in the midbrain substantia nigra of a mouse exposed to
MPTP. The rostroventral section of the substantia nigra compacta was taken from horizontal
slice of the mouse brain. The left section shows the TH immunoreactivity from a mouse
offspring that was preexposed to PBS during G8-12 of the pregnant dam. The right section
shows the TH inmmunoreactivity of a mouse offspring that was exposed to 10 mg/kg of
MPTP during G8-12. The study shows that marked reduction of TH-I occurred in the mouse
that was exposed in utero to MPTP (right).
4.7.3. Prenatal effect of MPTP on the Nissl Stained substantia nigra

The effect of prenatal exposure to MPTP on cellular distribution pattern in the substantia
nigra, compacta of C57BL/CJ mice is shown in figure 2 as low magnification Nissl stained
section of the 12 weeks old mice offspring. The differences in the cellular patterns for the
PBS and the MPTP exposed animals were not marked, but cellular pattern seems to occur in
the compacta zone for the PBS control as compared to the mouse that was exposed to MPTP,
in which more scattered smaller cells can be seen in the medial (M) to rostral (R) zone of the
substantia nigra (figure 1). The proportion of neurons to glia cells are unknown and are yet
to be determined.
5. The inducing, precipitating or superimposing stage of the hypothesis

PD shares some characteristics with aging and the incidence of PD is higher in the aged
individuals, but only a relatively small number of elders (about 0.3%) developed full-blown
PD, therefore, since PD is sporadic it would appear that a predisposition exists for the
disorder. The individuals that developed PD may have been predisposed or susceptible
throughout their lives, and they develop PD symptoms when metabolic changes associated
with getting older caused further harms to the nigrostriatal DA neurons and reduced the
number of neurons. The precipitating effects may be due to various factors, such as changes
that allow molecules that serve normal functions early in life to become toxic via direct or
indirect ways, such as the production of toxic byproducts, for example. The exposure to
DA and Metabolites
(ng/mg protein)
Prenatal
Exposure.
DA
PBS
DOPAC
MPTP 10mg/kg
PBS
MPTP 10mg/kg
HVA
PBS
3-MT
MPTP 10mg/kg
PBS
MPTP
10mg/kg
Postnatal MPTP Challenges (mg/kg)

0 (PBS)
10
20
30 mg/kg
16.40 2.0
34.5 1.7
141.0 5.50
157.3 17.3
[89.57]
[78.06]
[10.35]
[0.0]
3.95 1.0
[97.49]
1.95 0.41
[62.5]
135.6 4.80
[13.80]
5.2 0.76
[0.0]
5.9 0.88
[+13.46]
48.0 7.10
[69.96]
6.00 1.00
[15.38]
1.04 0.96
[80.0]
28.0 2.0
[82.20]
3.3 0.4
[36.53]
0.46 0.58
[91.15]
18.2 0.80
[0.0]
15.2 0.80
[16.48]
1.6 0.20
[0.0]
17.5 1.00
[3.85]
9.4 0.66
[48.35]
1.2 0.15
[25.0]
0.45 0.11
[65.38)
9.84 0.6
[45.93]
8.3 2.1
[54.39]
0.75 12
[53.22]
0.41 0.33
[92.11]
6.0 0.47
[67.03]
4.7 0.70
[74.17]
0.54 0.11
[66.25]
0.32 0.05
[80.0]
0.32 0.06
[80.0]
0.54 0.12
[66.25]
Table 2. Postnatal effects of MPTP in mice offspring exposed to in utero MPTP or PBS. Effects of
postnatal MPTP (10, 20, 30 mg/kg) on striatal DA, DOPAC, HVA and 3-MT in 12 weeks old mice
offspring exposed to prenatal MPTP or PBS. The percent changes based on the normal PBS population
levels are enclosed by brackets below the respective concentrations. The results show that postnatal
MPTP was more effective in reducing DA and its metabolites in the offspring that were exposed to
prenatal MPTP. However, for the 20 and 30 mg/kg doses of MPTP the significance of the postnatal,
precipitating concept was masked because those doses of MPTP also markedly reduced DA and its
metabolites in the prenatal PBS offspring.
exogenous toxic insults may also occur. This is represented by the outbreak of the 1919
encephalitis lethargic epidemic (Ravenholt et al, 1992) that precipitated PD symptoms among
some of those that were affected by the encephalitis virus. Whether the inducing, precipitating
or superimposing stage is due to metabolic changes or exposure to toxins, it should be noted
that the effects do not have to be specific to cause the expression of the specific symptoms of
PD, since the incidence during the first stage marks or sensitizes the nigrostriatal system,
accordingly, any toxin or any change that can cause further harm to neurons, even in a general
way, will affects those neurons that were made fragile.
5.1. Testing the inducing, precipitating or superimposing stage

We have shown that MPTP can be used to model the inducing, precipitating or
superimposing stage. This was demonstrated in our studies in which we found that the
postnatal administration of MPTP to 12 weeks old offspring, that were exposed in utero to
MPTP earlier, during the developmental stage of the NS DA neurons, showed dramatically
reduced levels of DA and its metabolites, as compared to similar mice that were exposed to
the PBS treatment. The magnitude of the changes matches the level seen in PD, when
compared with the normal population, or the PBS controls (table 2). The 10 mg/kg dosage of
MPTP given to the mice that were exposed to prenatal MPTP caused the most dramatic
reduction of DA and its metabolites, as compared to the PBS control (Table 2, column 3 vs. 4
showing values for prenatal PBS vs. prenatal MPTP). The 20 and 30 mg/kg of postnatal
MPTP markedly reduced DA in the prenatal exposed MPTP mice, but these dose levels of
MPTP also caused dramatic reductions of DA and its metabolites in the prenatal PBS mice,
as well, so the differences between the prenatal MPTP and the prenatal PBS were not as
dramatic (Fig 2, column 3 vs. 5 and 6 showing values for prenatal PBS vs. pre natal MPTP).
6. Analogy that depicts the two stages of affliction hypothesis

The two stages of affliction hypothesis for PD may be best illustrated by an analogy of a
motor vehicle tire that was manufactured with a specific defect due to poor quality steel
cords imbedded in the carcass or the body of the tire, during a critical period in the
manufacture of the tire. The tire shows all of the characteristics of normal tires, but on
exposure to the roadway the frictions that cause normal wear in tires turn out to cause
serious failure in the defective tire. An inspection of the failed tire will show specific failure
of the steel cords. The subtle imperfection that occurs during the manufacture of the tire
may be seen as the sensitization factor that tags the tire for the specific type of failure that
occurs under normal usage. In this scenario, such a normal tire usage may constitute the
period for the precipitating stage, the tire serves to depict the human brain, the cords depict
the nigrostriatal dopamine neurons with their far-reaching axonal projections, and the
roadway-frictions represent the wear-and-tear of living that increases as a function of age.
The two stages of afflictions or the sensitization-precipitating hypothesis for PD may also
explain the discordance for PD in monozygotic twins. The life-long personality difference
between monozygotic twins discordant for Parkinson's disease suggests that the process
responsible for the disorders of PD has its inception early in life (Ward et al, 1983). The
developmental personality of the member of the monozygotic twins who developed PD was
found to be more introvert but since being an introvert is not usually abnormal within the
population, it may be deduced that at least a second factor should be involved in causing
the PD in the affected twin. The primary factor could be the early changes that render the
nigrostrital DA neurons susceptible and also reflected or coincide with personality
difference. The second factor for the disorder expression may be related to the regression in
dopamine cells that occurs during aging (see McGree et al 1977).
7. Special cases of PD may involve early-life and multiple neuronal

groups
The Guam amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) may
represent an incident of PD in which wide-scale neuronal damage occurred during the
sensitization stage, and the wear-and-tear of living or the aberrations associated with aging
take their toll later in life. In other words, the nigrostriatal dopaminergic neurons that were
impaired during the fetal development degenerate to the threshold level that causes PD
symptoms. Above threshold neuronal death also occurred for the nucleus basalis of Meynert
acetylcholinergic neurons and cortical neurons involve in memory and cognition and caused
the dementia phase of ALS-PDC syndrome (Oyanagi, 2005). The lower and upper motor
neurons systems that control skeletal muscle contraction also died to cause the amyotrophic
lateral sclerosis phase of the disorder. The theory is based on the report that the ALS-PDC or
otherwise PDC-ALS is essentially the convergence of three disorders. Patients with PDC
showed the signs of rigidity, tremor and bradykinesia (Oyanagi, 2005), the classical signs of
Parkinsons disease as well as dementia (Oyanagi, 2005), the main sign of Alzheimers disease.
The ALS phase of the Guam ALS-PDC disorder has been reported to be essentially similar to
those of classic ALS. Moreover 5% of the patients with ALS subsequently developed the total
clinical symptoms of the ALS-PDC and 38% of the patients with PDC eventually developed
the PDC-ALS syndrome (Elizan, et al, 1966; Oyanagi, 2005). So the PDC syndrome may be
based on the exposure of the fetus to the cycad toxin during the period of the neurogenesis of
both nigrostriatal DA neurons and nucleus basalis neurons. The duration of the toxic exposure
of the patients may have been long enough to coincide with the neurogenesis and migration of
the nigrostriatal DA neurons as well as the nucleus basalis of Meynert acetylcholinergic
neurons. For the ALS patients, it is proposed that the exposure to the prenatal toxin coincides
with the birth of upper and lower motor neurons and causing deleterious effects early in life
that sensitized them to stress that occurred later in life. The higher 38 percent of patients with
ALS may be matching to the longer neurogenesis and proliferation period for the related
motor neurons and therefore longer fetal exposure time.
7.1. Proposed fetal basis for the Guam ALS-PDC disorder

The proposition that beta-methylaminoalanine (BMAA), a toxin found in flour produced
from the Cycad plant and eaten as food, caused ALS-PDC (Spencer et al, 1987), is of interest.
It was also claimed that the basal ganglia symptoms were produced in monkeys fed BMAA
(Spencer 1966), but this claim was disputed on the basis that the dosage used was far too
high to represent the amounts that are eaten by human (Ince and Codd, 2005; McGree and
Steele, 2011), and the disease produced in the monkeys was a classic acute toxicity model
(Ince and Codd, 2005), rather than the progressing model of the ALS-PDC seen in the Guam
patients. Moreover, the disease occurred in patients who had not used cycad products for
many years (Sacks 1998), again suggesting the fetal basis for this ALS-PDC disorder. The
risk of ALS-PDC was carried by migrants who had resided on Guam for the first 18 years of
life (Ince and Codd, 2005), suggesting that early exposure is important for those who
developed the ALS/PDC disorder, and the disorder takes over 35 years to develop, which is
a very long time for a metabolic toxin to cause direct toxicity, and this also deviates from the
short-term toxic models that have been presented.
It would be surprising that a major toxin consumed as a major source of food by several
families would be so limiting in the number of individual within a family who were
affected. In other words, if the ALS-PDC syndrome is due to a single-stage bout of toxic
exposure, it would be expected that the toxin, which is ingested regularly as food, would
affect a larger proportion of the group. So, it is apparently more reasonable to propose that
the individuals that developed the ALS-PDC in Guam were exposed during the period of
vulnerability of the nigrostriatal dopaminergic neurons, the nucleus basilis of Meynert
acetylcholinergic neurons and the upper and lower motor neurons. They bourne the scar of
the early exposure that pair with the changes that occur during aging to precipitate the ALSPDC syndrome later in life. The sensitization-precipitation concept may be true also for the
PD-like toxicity caused by MPTP in the later years of the 70s to the 80s. This may be so
because not all individuals who were exposed to intravenous MPTP eventually developed
full blown PD symptoms. Those that developed the symptoms of PD were probably
predisposed with less resilient nigrostriatal neuronal set, and those that were spared had
highly resilient nigrostriatal dopaminergic neurons. It means therefore, that most cases of
PD may be caused by encounter made during the stage of neurogenesis and development of
the nigrostriatal dopamine neurons, and that aging, the key risk factor for PD, precipitates
idiopathic PD. The progressive nature of idiopathic PD may be based on the fact that aging
is relenting and progressive in its own right.
8. S-adenosyl-L-methionine (SAM): A model precipitating factor for

Parkinsons disease
S-adenosyl-L-methionine (SAM) is presented as a likely precipitating factor for PD. SAM is a
naturally occurring and ubiquitous molecule derived from methionine and ATP (Cantoni
1953). It is one of the most reactive and important biochemical (Kotb and Geller, 1993), but
its activity seems to be harnessed by the limits and the control placed on its synthesis. SAM
is apparently synthesized on demand and rapidly utilized by several enzymes, as the
biological methyl donor (Cantoni 1953), for trans-sulfuration reactions and in the synthesis
of polyamine (Andres and Cederbaum 2005). As the biological methyl donor, SAM is the cofactor for several methyl transferases, including catechol-O-methyl transferase (COMT) and
indole amine methyl transferase. COMT transfers the methyl of SAM to dopamine (DA) to
produce 3-methoxytyramine and to norepinephrine (NE) to produce normetaphrene and by
doing so SAM terminates the synaptic activities of DA and NE, via irreversible reactions.
SAM also serves to methylate N-acetyl-serotonin, via indoleamine methyltransferase to
form melatonin and in the process may deplete serotonin (5-HT). These are major metabolic
processes since DA, NE and 5-HT are important in synaptic transmission and in behavior
(Agnoli et al, 1976) and are reported to be depleted in PD. So, SAM is a highly reactive
endogenous molecule.
The injection of SAM into the cerebral ventricle of rodents produced symptoms that are
similar or identical to those described for PD, including hypokinesia, rigidity, tremors
(Charlton and Way 1978), the loss of DA, loss of striatal and substantia nigra tyrosine
hydroxylase (Charlton, 1990; Charlton and Crowell, 1995; Crowell et al, 1993) and loss of
neurons in the substantia nigra (Charlton and Mack, 1994).The PD-like changes that
occurred following the cerebral ventricular administration of SAM are based on very logical
and mechanistic grounds, since SAM reacts avidly with L-dopa and DA and reduced DA.
More importantly, the loss of DA is the hallmark of PD disease, and the methylation of DA
at the synapse (Axelrod, 1965) terminates the neurotransmitter activity of DA; a process that
irreversibly destroys the dopamine molecule by covalently converting it to 3methoxytyramine. SAM also drives the synthesis of phosphotidylcholine (PTC) (Hirata et al,
1981) that is accompanied with increases in lyso-PTC (Lee and Charlton 2001), a potent
membrane damaging surfactant. It has been shown also, that SAM interacted with and
methylated DA receptor protein and inhibited DA receptor binding (Lee and Charlton,
2004). In addition, the carboxylmethylation of protein, including DA receptor protein, by
SAM, generates methanol (Axelrod and Daly, 1965), formaldehyde and formic acid (Lee et al
2008), reactive byproducts that can cause irreversible and accumulative damaging changes
to cells and cellular constituents. Although the biological role of methanol, formaldehyde
and formic acid are not viewed with much significance, these molecules are likely to be of
primordial origin, helping to shape the destiny of life. They are produced in the body and
are extremely reactive. The activity of SAM is also increased during aging (Mays and Borek
1973; Stramentinoli et al, 1977; Gharib et al, 1982; Sellinger et al, 1988), a critical period for
cellular attrition and a stage of life during which the symptoms of idiopathic PD are seen.
Today SAM is well studied as the major driver of the epigenetic modification of various
genes. The biochemical control that SAM exhibited is remarkable on the basis that SAM is
the limiting factor for dozens of methyltransferases, so any increase or decrease in the level
of SAM serves as a key driving force for most methylation reactions.
8.1. Common markers exist for methylation and parkinsonism

A review of the results from various laboratories, include our own, shows that various
biochemical, functional, anatomical and other markers are common to PD and to the
methylation process (Table 3). Metabolites and byproducts of SAM, such as N-methyl
dopamine, 3,4-dimethoxy-dopamine, N-methylsalsolinol (Maruyama, et al, 1996; Naoi et al,
2002; Matsubara et al, 2002) and harman and norharman (Kuhn, et al, 1996) are elevated in
Biological Events
Biochemical changes
Decreased dopamine
Decreased norepinephrine
Decreased serotonin
Decreased melanin
Decreased tyrosine hydroxylase
Increased Ach activity
Increased HVA/DA
Increased DIMPEA
PD relevance
Effect on/of SAM
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Functional defects
Hypokinesia
Tremors
Rigidity
Abnormal posture
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Anatomical impairments
Nigrostriatal damage
Loss of DA/TH neurons
Yes
Yes
Yes
Yes
Other markers
Older ages
L-dopa
Methionine
N-methyl tetrahydroisoquinoline
Methyl beta carboline
MPTP/MPP+
N-methyldopamine
N-methylsalsolinol
Homocysteine
MPP+
Manganese
Lyso-phosphotidylcholine
Nicotinamide-N-methyl-transferase
More prevalent
Alleviates
Aggravates
Causes/in PD brain
Causes
Causes
Found in
Found in
Found in
Aggravates
Aggravates
PD-like effects
High in CSF
High activity of SAM

Depletes SAM
Increased SAM
SAM metabolite
SAM metabolite
Enhances methylation
SAM metabolite
SAM metabolite
SAM metabolite
Increased SAM activity
Increased SAM activity
Increased by SAM
SAM is the cofactor
Table 3. Many biological changes seen in PD correspond with the effects of SAM. The table shows the
parallel relationship between changes associated with Parkinsons disease and with the effects and
biochemical activities of S-adenosyl-L-methionine and its metabolites. A one-one relationship is shown
in the activities listed.
the CSF of PD patients and homocysteine (Lee et al, 2005) may cause PD like toxic changes.
In addition, methyl-beta-carboline was reported to cause PD-like changes (Collins, et al.
1992; Gearhart et al, 1997). Furthermore, it has been shown that the tissues of PD patients
methylate nicotinamide greatly higher than tissues of the control patients (Willams et al,
1993); and that nicotinamide methylation is proposed to be a key factor in the development
of degenerative diseases (Williams and Ramsden, 2005). The enzyme, nicotinamide-Nmethyltransferase, that transfers the methyl group from SAM to nicotinamide, was shown
to be high in the CSF of PD patients (Aoyama et al, 2001) and N-methyl-nicotinamide was
also higher in the brain of PD victims as compared to the control (Williams and Ramsden,
2005). So, as shown, many biological changes seen in PD correspond with the effects of
SAM, its enzymes and its metabolites (table 3).
8.2. Actions and effects that support the role of SAM as a precipitation factor in
PD
If a secondary precipitating factor is associated with PD, it would more likely fits as a toxic
metabolite that is associated with aging. Such a metabolite would be expected to be very
reactive. It would show age-related increases in activity, would have a narrow index of
safety so that even slight increases would cause toxic reactions. It should react with normal
biochemicals that are critically needed on a moment-by-moment basis for the maintenance
of essential functions. Moreover, the metabolite should react with biochemical that are
found to be modified during the course of PD, for example, DA that is depleted in PD and
which is an avid methyl acceptor. In addition, the mode of reactivity of the metabolite
should explain others changes that are related to the degenerative disease process, such as
the effective therapy for PD and the development of tolerance to the therapeutic agent. So,
an evaluation of S-adenosyl-L-methionine (SAM), the biological methyl donor, based on the
above criteria, indicates that it fits the role of a precipitating factor for PD. Again, it is an
endogenous molecule, its activity is increased during aging, it is very reactive, it has a
narrow index of safety, it controls the metabolism of specific chemicals that are modified in
PD, the major drug for PD, which is L-dopa, reacts avidly with SAM and L-dopa, in turn,
induced methionine adenosyl transferase, the enzyme that produces SAM (Benson et al,
1993; Zhoa et al, 2001). Moreover, as mentioned above, several SAM-induced changes seem
to be associated with the neuronal degeneration and many of the biochemical changes that
occur in PD.
8.2.1. Age-dependent increases in SAM-dependent methylation

The activities of SAM, denoted by increases in its synthesis and utilization, are increased
during aging. This has been reported as, an age-related increase in methionine-adenosyl
transferase, the enzyme that produces SAM, increases of various methyl transferases, and
the accumulation in products of SAM-dependent methylation reactions, including
homocysteine and adenosine (Mays et al 1973; Stramentinoli et al, 1977; Sellinger et al 1988;
Gharib et al 1982). It should be noted that a decrease in the absolute concentration of SAM in
rats was reported to be related to aging (Baldessarini and Kopin, 1966) but the reduction
was apparently due to increases in the turnover of SAM that also occurred during aging
(Stramentinoli et al, 1977).
8.2.2. SAM depletion of biogenicamines may occur in PD

In the presence of catechol-O-methyltransferase and other transferases SAM serves as a
cofactor in the methylated metabolism of several biogenic amines, including DA and
norepinephrine, by donating its reactive methyl group mainly to receptive hydroxyl of the
molecular ring and the nitrogen of the ethylamine side chain (Axelrod, 1965). SAM
dependent methylation is the most important mechanism in mammals for the inactivation of
catecholamine (Lambrosse et al 1958, Axelrod et al, 1965), consequently SAM is an
important factor in controlling the neuronal levels of the biogenic amines. The decreased
levels of DA (Hornykiewicz, 1966), norepinephrine (Erhinger and Hornykiewicz, 1960) and
serotonin (Bernheimer et al, 1961) observed in PD could be explained by an increase in the
methylation of DA, norepinephrine and of N-acetyl-serotonin. The methylation of DA may
also explain the increase ratio of homovanillic acid (HVA) to DA (HVA/DA) in PD and the
increased level of 3,4-dimethoxyphenylethylamine, the dimethoxy metabolite of DA, that
was reported to be contained in the urine of PD patients. More importantly, the DA derived
alkaloid, N-methyl-(R)-salsolinol, was shown to occur in the human brain, accumulates in
the nigrostriatal system and may play a role in PD (Naoi et al, 2002). An increase
SAM-dependent methylation may also help to explain the pharmacology of L-dopa, in
treating the symptoms of PD, because L-dopa is not only converted to DA, but it also reacts
avidly with SAM, and depletes SAM. SAM dependent regulation of biogenicamines is
achieved by methylated catabolism as well as by increasing synthesis, because it has been
shown that preincubation with SAM caused activation of tyrosine hydroxylase in the corpus
striatum of rats (Mann and Hill, 1983). These and other outcomes suggest that SAM is
functioning both intra- and extra-neuronal, therefore its bio-availability at specific sites
should be critical in determining the up or down regulation of the activity of
biogenicamines. SAM activation of tyrosine hydroxylase (Mann and Hill, 1983) may help to
explain the increase in DA turnover that occurs in PD. An increase in the methylation of Ldopa and DA will shunt tyrosine toward the production of L-dopa and L-dopa toward the
production of DA, thus, tyrosine will be shunted away from the synthesis of melanin, a
process that may help to explain the reduction of melanin in the substantia nigra of PD
patients: noting that melanin is a product of tyrosine. Likewise, SAM also methylates
phosphotidylethanolamine to produce phosphotidylcholine and phosphotidylcholine, in
turn, is metabolized to generates choline molecules for the synthesis of acetylcholine. So, an
increase in methylation could conceivable increase the level of acetylcholine and
acetylcholinergic activity that occurred in PD, and which may form the basis for the utility
of anticholinergic agents in the treatment of PD symptoms.
8.2.3. Mechanisms and selectivity of SAM for the basal ganglia

Conditions that increase the rate of methylation, for example aging (Sellinger et al 1988),
may precipitate PD in individuals with susceptible DA neuronal population. In individuals
with the normal complement of substantia nigral DA neurons the same level of methylation
may represent an age-dependent normal regression of cell population, because the critical
cell level that will result in PD would not be reached. Thus, the final effects of an increase in
methylation in persons with normal populations of DA neurons would be different degrees
of aging. Besides aging, other factors that facilitate an increase in methylation ought to be
emplaced. It turns out that (i) the chemistry of the basal ganglia, (ii) the anatomical and
physical state of the basal ganglia and (iii) the functions that are controlled by the basal
ganglia coexist in a cooperative way to facilitate the uniqueness of SAM as the methyl donor
and as a putative precipitating factor for PD.
For the chemistry of the basal ganglia, the methylation of DA and the methylation of
phosphotidylethanolamine may be of major importance. First, the methylation of DA by
SAM depletes DA at the synaptic cleft. This is an irreversible reaction that also generates 3methoxytyramine, a metabolite that has been shown to competes with DA for its receptor
binding (Charlton and Crowell, 2000). So, the reaction of SAM with DA and the generation
of an competing metabolite will not only depletes DA, but also will interfere with the
binding of DA to its receptors, which is consistent with a SAM-induced dopaminolytic state.
SAM also methylates phosphotidylethanolamine to produce phosphotidylcholine, and, as
mentioned above, to produce choline for the synthesis of acetylcholine. In addition,
phosphotidylcholine is readily hydrolyzed to form the toxic surfactant, lysophosphotidylcholine (Lee et al, 2001; 2005). The reaction is also relevant on the basis that
lyso-phosphotidylcholine is a potent surface-active agent that will damage cellular vesicles
and nerve ending, and can contribute to the progression of the degeneration that occurs in
PD. The biochemical peculiarity of the basal ganglia, therefore, includes the fact that the
neostriatum contains large quantities of L-dopa, DA and norepinephine that are avid methyl
acceptors, so they utilize high levels of SAM. SAM is also required for the methylation of
phospholipid and the synthesis of acetylcholine, so the neostriatum is a high utility site of
SAM, or a chemical sink for, SAM.
The precise functions of the basal ganglia marked it for visible impairments. The basal
ganglia dopaminergic system controls precise articulation of the hands, finger, lips and
whole body to support emotional expression, gesture and feelings. Therefore in the awaking
human the neostriatum is constantly under stress to maintain the delicately balanced and
fine-tuned processes that it controls, so slight impairments of the nigrostriatal system will
upset the postural balances and precise muscle regulations and will cause visible
impairments, that are seen as PD, even when such a degree of impairment or degeneration
would not be physically obvious if occurred in other systems. SAM-related age-related
changes may also affect vision and hearing, but the changes in the quality of life are not of
the same magnitude as seen when the basal ganglia is impacted.
The anatomical or physically states of the basal ganglia also make this structure very
accommodative to the effects of an increase in SAM, because SAM, which is very water
soluble, will accumulate in the cerebral spinal fluid (CSF). In the CSF SAM is in close
proximity to the neostriatum, which courses along and protruded into the lateral ventricle
and contains the sensitive dopamine nerve terminals. Studies have shown that the
administration of SAM into the lateral ventricle damaged the delicate ependymal cell barrier
that separates the CSF from the caudate nucleus neuronal environment. By doing so, SAM
gained access to the neostriatum, where it can deplete DA (Crowell et al, 1993), can
methylate phospholipids (Lee and Charlton 2001) and DA receptor protein (Lee et al, 2004)
and generate methanol, formaldehyde and formic acid (Lee et al, 2008) that are damaging to
nigrostriatal dopamine nerve endings. These metabolites, especially formaldehyde will
result in permanent changes to the dopaminergic neurons. Interestingly, in a more recent
study, we found that the co-administration of a retrograde neuronal tracer with SAM into
the lateral ventricle caused the labeling of cells in the substantia nigra, indicating that
molecules placed in the lateral ventricle can gain access to the caudate nucleus DA nerve
endings.
The increase in methylation can caused other significant changes, for example, the
utilization of SAM imposes a great demand on ATP, because for every mole of DA
methylated at the 3-OH and 4-OH positions 2 moles of ATP are utilized to replenish the
utilized SAM and for every mole of phosphotidylethanolamine that is methylated to form
phosphotidylcholine 3 mole of ATP are required to replenish SAM. Furthermore, the
carboxyl methylation of protein by SAM will increase the isoprenylation of the proteins and
each farnesyl molecule that is utilized requires 3 moles of ATP for its synthesis and each
geranyl-geranyl requires 4 moles of ATP for its synthesis. So, an increased methylation will
require increased production of ATP, which increases oxygen utilization and the probability
of generating reactive oxygen species. In addition, 1 mole of potentially toxic homocysteine
and 1 mole of adenosine may be produced for every mole of SAM utilized, and huge
amounts of adenosine will be produced as a result of the metabolism of ATP to replenish
SAM. The depletion of ATP may be relevant in this connection, because inhibition of
mitochondrial oxidation and ATP reduction are proposed to be involved in the actions of
MPTP or MPP+. It is well understood that SAM-dependent methylation is a normal
physiological process, so for one to imagine how SAM may be involved in PD it should be
understood that the symptoms of PD are due directly to dopamine biochemical deficiency
and indirectly to the neuronal degeneration. This is so because drugs, such as L-dopa and
DA receptor agonists relieve the tremors and other symptoms of PD, in spite of the fact that
the permanent neuronal degeneration remains. Furthermore, the syndrome of PD wax-andwane, which, cannot be explained by the existence of a permanent degenerated neuronal set.
These examples show that the symptoms of PD, such as tremor and freezing, are striatal
biochemical deficiency symptoms, due to the loss of dopamine as a result of the neuronal
degeneration.
In spite of the doubts about the methylation concept, it is of interest that most of the other
hypotheses concerning the genesis of PD cannot explain many of the changes that are seen
in PD. One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxyl-dopamine
(6-OHDA) serve as the most important chemical models for PD. Their efficacies are mostly
related to the targeted nigrostriatal cell death, but these agents do not cause changes that
reflect the whole spectrum of PD symptoms. For example, MPTP does not cause PD-like
symptoms in the rat, which also has a nigrostriatal dopamine system, but SAM does
(Crowell et al, 1992; Charlton and Mack, 1994).
9. Conclusion
The abberrations that cause the nigrostriatal degeneration that result in Parkinsons disease
are unknown. Since about 90-95% of all cases of PD are not due to genetic changes, it means
that the environment plays a major role in the cause of PD. The environment is not restricted
to the toxins that might be involved, but includes the biochemical melieu that the
nigrostriatal cells encounter from their origin to the outcome that causes them for die. So,
the encounter with inappropriate biochemicals and inappropriate levels of the appropriate
biochemicals may occur, and the outcome will vary and will be restricted to the nigrostriatal
neurons or will involve other neuronal sets. This type of encounter will produce the
syndrome that are eventually expressed and may include symptoms related to nigrostriatal
damage only, but may be accompanied with other syndrome. So the expression of
symptoms in addition to the classical PD other symptoms, suggests that nigrostriatal
neuronal impairment may be accompanied with the impairments of other neuronal groups.
These may include the basal nucleus of Meynert acetylcholinergic neurons that are
degenerated in Alzheimers disease (AD) and the upper and lower motor neurons that are
involved in the cause of amyotrophic lateral sclerosis (ALS). So, the existence of the Guam
amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC, suggests that the
factors that cause PD are not specific for the nigrostriatal neurons, but will affect other
neuronal groups, as well.
For PD, it is suggested that the nigrostriatal dopaminergic neurons were exposed by chance
encounter during a vulnerable stage of development of the neuronal set. Since aging is the
key risk factor for PD, it also means that at least two stages of afflictions are involved in the
cause of PD. Evidence and circumstance suggest that the first stage occurs in utero during
the neurogenesis and development of cells to form the substantia nigra dopaminergic
phenotype. The neuronal set is harmed in a subtle way that does not cause visual
symptoms, but the sub-threshold effects weakened the resilience of the neurons so that the
stress encounter during the course of living causes further harm to the already affected
neurons and precipitates the symptoms of PD. So, the first impairment may occur during
the neurogenesis and development of the nigrostriatal dopamine neurons by inappropriate
levels of regulatory molecules or by toxins. An increased activity of cyclic-AMP-dependent
protein kinase A, for example, may antagonize the signal for sonic hedgehog protein and
blocked the induction of dopamine neurons (Hayes et al, 1995). The exposure to alkaloids,
such as colchicine or vinblastine may also occur, and these alkaloids may interfere with the
development of the cytoskeleton, with long-term and sub-threshold levels of effects. The
stress of aging that causes globally deteriorating change will then take a toll on these low
resilient neuronal sets to precipitate the symptoms of PD. The prenatal and postnatal effects
can also explain the occurrence of juvenile PD, which would involve the substantia nigral
dopamine neurons that were affected in ways that make them less resilient and more
sensitive to age-related stress, so a short course of living would be enough to precipitate the
symptoms of PD in the young individual. The Guam ALS-PDC cases are proposed to be
caused by the exposure to the Cycad toxin during the neurogenesis and development of the
nigrostriatal dopamine neurons, the basal neucleus of Meynert acetylcholinergic neurons
and upper and lower motor neurons. The exposure caused subthreshold harms to those
neuronal sets and they failed before other major groups of neurons during the course of
aging.
The hypothesis that neurodegenerative disorders, such as PD and others have their origin in
the womb is in line with normal physiology, since the lives of all mammals have their origin
in the womb. If the hypothesis is tested to be true further investigation will identify the
specific agents and/or the mechanisms that may be involved in the sensitization stage and
measures could be adapted to protect the vulnerable neuronal groups during critical stages
of fetal development.
Author details
Clivel G. Charlton
Meharry Medical College, USA
Acknowledgement
The author wishes to thank Gladson Muthian, Ph.D., Lemuel Dent, MD., MS; Veronica
Mackay, B.S., Marquitta Smith, B.S. and Brenya Griffin, B.S. for their support of science in
our laboratory. Supported by NIH NINDS R21NS049623, RO1NS28432 and R01NS31177
and Bernard Crowell, Jr. MD, Ph.D., Little Rock AR.
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Chapter 3
Basal Ganglia and the Error Monitoring

and Processing System: How Alcohol
Modulates the Error Monitoring and
Processing Capacity of the Basal Ganglia
http://dx.doi.org/10.5772/53945
1. Introduction
The Basal ganglia as a subcortical relay station at the base of the forebrain is largely
involved in processing of information, cognition, and movement (Gehring et al. 1993;
Mathalon et al., 2003; Nick et al., 2003). Over the last century, knowledge about the basal
ganglia has been acquired mainly from animal research, and pathologies that affect the basal
ganglia in humans. In pathologies such as Parkinsons and Huntingtons diseases the basal
ganglias functions are greatly affected (Beste et al., 2009; Holroyd et al., 2002).
Apart from brain pathologies, psychotic substances can affect the normal functioning of the
basal ganglia (Goldstein et al., 2007). Alcohol is one of the psychotic substances that affect
the functions of the basal ganglia (Goldstein et al., 2007; Holroyd & Yeung 2003; Goodlett &
Horn 2001).
Many substances that cross the blood brain barrier can affect the normal functioning of the
basal ganglia either indirectly or directly (Buhler et al., 1983). The direct effect occurs, if the
substances reach the basal nuclei. The indirect effect happens when pathways linking other
brain regions (sub-cortical pathways) are affected. In addition, the metabolic products of
these substances can exert their effect on the neurons of the basal ganglia or on the
pathways linking the basal ganglia (Buhler et al., 1983; Deitrich et al 2006; Salvador &
Alfredo 2010).
In recent years, the basal ganglia have been implicated in error commission (Holroyd &
Yeung 2003). In fact, in pathologies involving the basal ganglia, research has shown that
error commission rate is significantly higher, compared to controls (Holroyd et al., 2002).
2012 Welcome and Pereverzev, licensee InTech. This is an open access chapter distributed under the
terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
In this chapter, we examined the effect of alcohol on the functions (precisely the error
monitoring and processing capacity) of the basal ganglia.
2. Materials and methods

Literatures for this study were searched in Pubmed, DOAJ, Embase, Google scholar, African
Online Journals, and Scopus. The following keywords were used in the search processes:
Alcohol and error detection; Alcohol and correction; Alcohol and error commission; Alcohol
and error processing (OR monitoring); error monitoring and processing system; basal
ganglia; error and the basal ganglia; alcohol and the basal ganglia. For details on the study
materials and methods, see Welcome et al., 2010. In addition, we analyzed our recent data as
regards to error commission dynamics in alcohol users and non-alcohol users. Data from
our recent publications regarding error commission and effectiveness of cognitive functions
in alcohol users and non-alcohol users were also examined.
3. Basal ganglia and the error monitoring and processing system

The error monitoring and processing system (EMPS) located in the substantia nigra of the
midbrain, basal ganglia and cortex of the forebrain, plays a leading role in error detection
and correction. Although, it is widely known that the main components of EMPS are the
dopaminergic system and anterior cingulate cortex, it appears that the basal ganglia also
play a crucial role (Welcome et al., 2010).
Recent data suggest that error commission is tightly monitored by the basal ganglia, and this
anatomical structure remains an integral aspect of cognitive processing (Beste et al., 2009;
Holroyd & Coles 2002). Importantly, an increase in error commission is associated with
decrease in cognitive functions (Welcome et al., 2010, 2011). The basal ganglia are
adequately engaged with other brain areas and monitors error detection and correction
(Carter et al., 1999; Garavan et al., 2002; Holroyd & Yeung 2003). The functions of the EMPS
are dependent on the degree of phasic dopamine activity on the brain areas that process and
monitor error commission (Holroyd & Yeung 2003). Other neuromediators (GABA, glycine)
might also play crucial role (Wick et al., 1998).
3.1. Error commission: Different types, one source

Daily performances of humans are in most cases evaluated based on the outcome of
activities executed. The activity function is a measure of accuracy of performance (i.e. speed
of performance and the number of incorrect/correct tasks done). While the speed of tasks
might be controversial in some cases, error commission rate remains a useful parameter in
performance evaluation. For instance, in basal ganglia pathologies, error commission has
been found to significantly increase, whereas speed of task decreases. On the contrary, even
though error commission might increase in alcohol users, our data and those of other
authors show faster performance of tasks in this group of people (Welcome et al., 2010;
Schulte et al., 2001).
Basal Ganglia and the Error Monitoring and Processing System:

How Alcohol Modulates the Error Monitoring and Processing Capacity of the Basal Ganglia 67
The results of our research further stipulate that a normal physiological error commission
rate by humans who do not use alcohol is approximately 5%, whereas the rate for alcohol
users significantly exceeds 10% (Welcome et al., 2010). This is because the brain processing
of information has an automatic component, which means a basal level of error commission
for a normal physiological state. Lower error commission points to more effective
processing in those brain regions responsible for correct responses. Correct responses tightly
engaged a network comprising the left lateral prefrontal cortex, left postcentral
gyrus/inferior parietal lobule, striatum, and left cerebellum (Garavan et al., 2002; MarcoPallars et al., 2008; Endrass et al., 2012).
The evolution of error processing is a complex one. In comparative evolutionary studies,
there are evidences that suggest intrinsic error processes not only at the organismal level,
but also at the cellular and subcellular level (cellular and genetic errors) (Schulte et al., 2001;
Ochoa 2006; Takeuchi et al., 2005; Cohen & Ellwein 1991). Increased error commission seen
in the real world (organismal level of error commission) is the result of error processing
disorder at the neuronal level (Holroyd & Coles 2002). It is important to note that many
catastrophic cases (in aviation, for instance) are caused by error commission a failure in the
brains error monitoring and processing function or the so-called human factor. Further
study in this aspect will be of great importance to enhance safety and increase effectiveness
of mental performance, especially for the necessary contingents of people such as pilots.
There are different types of errors, but almost all types have one source the EMPS. In
experimental conditions, errors are made when subject press the incorrect button on a
keyboard (for example, in a Go/No-Go task) or did not pick the correct answer, or adhere
strictly to instructions (Stevens et al., 2009). These errors are further classified by some
authors as memory commission/omission errors; brain errors; cognitive errors etc. all from
one source the EMPS (Giesbrecht et al., 2007; Hurst 2008; Stevens et al., 2009). Error of
omission occurs as a failure to respond to tasks. The electrophysiological bases of these two
types of errors are outlined in a recent work by Krigolson & Holroyd (2007). Errors
committed in the medical setting (by medics) have been referred to as medical errors
which are cognitive errors of omission or commission (for review see Hurst 2008).
Another important question that comes into mind is how do we know an error is made?
Firstly, in an experimental condition, a deviation from the set goals will be decoded as error.
However, in certain cases, even the participants recognize the fact that they committed
error. So how does this happen? A search for the answer to this question is rooted in the less
researched Pe component following ERN (Pe component is briefly discussed below).
Research suggests that behavioral adjustment might represent a useful in error awareness.
There evidences suggest a close relationship among error commission, behavioral
adjustment and executive functions (Garavan et al., 2002; Marco-Pallars et al., 2008). The
awareness of errors might be the result of close engagement between executive functions
and the brain EMPS. Hence, it is probable that when executive functions (e.g. attention) are
closely engaged with the EMPS, error awareness increases. Furthermore, recent evidence
shows the capacity of the basal ganglia (through the basal ganglia-cortical pathways) to
implement successful performances that were initially produced by other brain regions,
indicating precise functional connections between basal ganglia circuits and the motor
regions that directly control performance (Charlesworth et al., 2012). Also, the basal ganglia
generate a variety of behaviors during execution of task and learn to implement the
successful behaviors in their repertoire to meet the target (Sur & Schultz 1999).
In electrophysiological studies, error commission is reflected in the reduced amplitude of
the Error Related Negativity, ERN (or Error Negativity, Ne) (Falkenstein et al., 2000;
Ridderinkhof et al., 2002), a negative deflection in the electroencephalogram with a
maximum in the midline of the frontocentral region of the scalp having a latent period
around 50-150ms (Falkenstein et al., 2000; Ridderinkhof et al., 2002).
The ERN amplitude might show gradual decrease for older adults (Pontifex et al., 2010).
However, because of amplitude difference across different age groups caused by gradual
increase in brain regions involved in error processing, the number of brain regions
responsible for error processing and monitoring may vary according to the age of the
subjects under analysis. Importantly, not only maturation of the neural systems that
identifies different errors account for this increase (Stevens et al., 2009), but also neural
plasticity. ERN is smaller for adolescents (Pontifex et al., 2010).
Nowadays, a growing body of data suggests that error commission is associated not only
with the early time-course ERN components of the electroencephalogram but also with a
successive neurophysiological late error positivity (Pe) following motor execution. The exact
cognitive and physiological processes contributing to these two components, as well as their
functional independence, are still not fully been unraveled (Vocat et al., 2008). The
occurrences of ERN and Pe involve activation of a distinct configuration of intracranial
generators during error commission. Pe peaks approximately at approximately 300ms after
erroneous actions (Vocat et al., 2008; Endrass et al., 2012).
For about two decades the Pe component has remained elusive and has become the subject
of a fierce debate in the scientific community (Falkenstein et al., 2000; Vocat et al., 2008; Dhar
M et al., 2011).
Several studies have suggested that the error positivity (Pe) reflect conscious error
awareness (Dhar et al. 2011; Garavan et al., 2002; Marco-Pallars et al., 2008). Although,
previous studies have disputed this view. According to Falkenstein et al. (2000) the Pe,
represent a error-specific component, which is independent of the ERN, and hence is
associated with a later aspect of error processing or post-error processing. Falkenstein and
coauthors (2000) further argue that the Pe reflects conscious error processing or the posterror adjustment of response strategies.
A recent report further supports the error awareness property of the Pe component. Endrass
and colleagues (2012) have recently shown that error awareness mainly influences the Pe,
whereas the ERN seems unaffected by conscious awareness of an error. This confirms that
the Pe is related to error commission. Hence this component is sensitive to the salience of an
error and that salience secondarily may trigger error awareness (for review see Endrass et
al., 2012).

For review on ERN and Pe amplitude see Amodio et al. (2006), Endrass et al. (2012), Pontifex
et al. (2010), Falkenstein et al. (2000).
3.2. Error commission in controls, and Basal ganglia pathologies

Because both ERN and Pe show promise for use in clinical setting for the diagnosis of
psychopathology (including basal ganglia pathologies), further research on these
components is necessary. To this end, reports clearly indicate that these error components
may represent a predisposition factor for behavioral disorders including substance use
disorders (alcoholism), brain (basal ganglia) pathologies (Olvet & Hajcak 2008; Franken et
al., 2010; Fein & Chang 2008; Van Veen & Carter 2006; Aarts & Pourtois 2010). Although,
there are controversies on whether or not the ERN actually has a diagnostic significance.
Studies have suggested that the ERN reflect a trait, and not a state factor (Pailing &
Segalowitz 2004; Olvet & Hajcak 2008). For a better appreciation of the usefulness of ERN
and Pe in psychopathology (including basal ganglia dysfunctions) a mathematical modeling
involving the second derivative of these components and segmental analysis might be
necessary which will give a glimpse into their importance for clinical diagnosis.
Besides alcohol and basal ganglia pathologies, sleep deprivation (or insomnia) is also a
factor for increase in error commission which might result in various catastrophes including
industrial and engineering disasters, motor accidents etc. (Mitler et al., 1988). This suggests
the presence of a circadian control mechanism in EMPS.
Vocat et al. (2008) found that the ERN correlates with the level of state anxiety, even in the
subclinical range, whereas the Pe correlates negatively with the total number of errors and
positively with the improvement of response speed on correct trials.
The mechanism of increase in error commission in people with basal ganglia dysfunction is
a complex one. A growing body of literature data suggests the involvement of attention
control mechanisms. For instance, patients with Huntingtons disease show great decrease
in the ability to assess various aspects of tasks (disorder in attention), resulting from a
disorder in action-selection processes. This obviously will lead to increase in error
commission in tasks (Beste et al., 2008). One recent study by Bocquillon and co-workers
(2012) suggests that basal ganglia pathologies results in resistance impairment to distracters
(which might actually, in most cases represent competing neural information), hence
providing more grounds for error commission. An electromagnetic tomography and
electrophysiological study involving the P300 found that, unlike in the controls, in patients
with Parkinsons disease, disruption of the frontoparietal network impaired resistance to
distracters, which resulted in attention disorders (Bocquillon et al., 2012). However, increase
in error commission may in part be the result of global cognitive impairment and inhibitory
control disorders (Gauggel et al., 2004).
In another study, Beste et al. (2006) assessed ERN amplitude in a speeded reaction task
under consideration of the underlying genetic abnormalities in patients with Huntingtons
disease. The findings of the researchers showed a specific reduction in the ERN, suggesting
impaired error processing. Furthermore, the ERN was closely related to the trinucleotide
CAG-repeat expansion. The authors concluded that the reduction of the ERN is likely to be an
effect of the dopaminergic pathology. And that the ERN might be a measure for the integrity
of striatal dopaminergic output function (Beste et al., 2006). This view is in direct agreement
with previous studies on the role of the dopaminergic system in error commission (Holroyd &
Yeung 2003). In contrary to the study of Beste and colleagues (2006), previous study by
Holroyd and colleagues (2002) did not find any difference in ERN amplitude between patients
with basal ganglia pathology (precisely Parkinson disease) and the controls. Although the
authors noted that the error-processing system associated with the ERN was not severely
compromised in the patient population that participated in the study.
Patients with basal ganglia pathologies have slower reaction time compared to controls
(Berry et al., 1999). It appears that time processing disorders might even be a more useful
factor to assess basal ganglia pathologies (Beste et al., 2007). In a time-estimation and timediscrimination task Beste et al. (2007) found deterioration of time-estimation processes in
symptomatic and even presymptomatic Huntingtons disease. However, timediscrimination processes were not affected. Time processing is a critical function of the
cortico-basal ganglia circuits (Jin et al., 2009). Although previous report has disputed the
involvement of the basal ganglia in timing (Aparicio et al., 2005). A general probation of the
components of error processing in various cultural groups, while controlling for factors such
as age, gender, educational level, various mental states, and psychopathologies is necessary.
4. Pathways of alcohols action on the error monitoring and processing

capacity of the Basal ganglia
For the first time in 2002, it was reported that alcohol consumption disrupts error
monitoring (Ridderinkhof et al., 2002). According to electro-physiological studies, the effect
of alcohol on the Error Monitoring and Processing System, EMPS is reflected in the reduced
amplitude of the Error Related Negativity (ERN) (Falkenstein et al., 1995; Ridderinkhof et
al., 2002), a negative deflection in the electroencephalogram with a maximum in the midline
of the frontocentral region of the scalp having a latent period around 50-150ms (Easdon et
al., 2005; Ridderinkhof et al., 2002; Welcome et al., 2010).
Even though the effect of alcohol on EMPS is documented, information on how alcohol
affects error monitoring and processing is scanty (i.e. the mechanism of alcohols effect on
EMPS remain adequately researched). Two co-researchers, Holroyd and Yeung in 2003 in
their review suggested that alcohols effect on error monitoring and processing is likely
indirect, not direct, and that the mechanisms remained unknown. They however suggested
that alcohol might modulate EMPS through its effect on the dopamine system. Recently, in
our review we suggested indirect mechanisms by which alcohol disrupts the EMPS
(Welcome et al., 2010). However, based on increasing evidences (Deitrich et al., 2006; Wick
et al., 1998; Quertemont 2004; Buhler et al., 1983), a direct disruption might also be possible,
especially, if we consider the possibility that receptors of neuromediators might have
alcohol pockets-receptors. It is reported that glycine and GABAA receptors may harbor
specific pockets for alcohol (Wick et al., 1998).

Figure 1. Pathways of alcohols action on the Basal Ganglia
Besides, it is known that alcohol readily crosses the blood brain barrier. In the brain, alcohol
can disrupt the transmission of signals through the basal ganglia/or the processing of
information by the basal ganglia. The following scenarios are possible (see fig. 1):
a.
b.
c.
d.
Direct effect of alcohol on the processing capacity of the basal ganglia by inhibiting
cellular processes, depending on the dose of alcohol;
Indirect effect of alcohol on the processing capacity of the basal ganglia by affecting
other brain areas connected to the basal ganglia;
Direct effect on neuromediators that modulate the processing of information in the
basal ganglia and/or associated brain pathways;
Action of alcohol metabolites (acetaldehyde; acetate; protein, lipid, enzyme & DNA
adducts of alcohol) on the processing of information in the basal ganglia and/or
associated brain pathways. The brain might contain alcohol metabolizing enzymes such
as ADH-1, ADH-2, ADH-3 (might play little or no role), CYP P4502E1 (Quertemont
2004; Buhler et al., 1983), although there might be a huge genetic variance. It important
to note that injection of acetate into the brain causes significant decrease in motor
function (Deitrich et al., 2006).
5. Theories suggesting alcohols effect on the error monitoring and

processing capacity of the Basal ganglia
There are at least five hypotheses & theories that might explain how alcohol use affects the
error monitoring and processing capacity of the basal ganglia. They are hypotheses of error
detection; reinforcement-learning theory; conflict-monitoring theory; the integrated conflict
monitoring-reinforcement learning theory; and hypothesis of alcohol-related glucosedependent system of error monitoring & processing (Holroyd & Coles 2002; Holroyd &
Yeung 2003; Welcome et al., 2010). Of these theories/hypotheses, only the reinforcementlearning theory; conflict-monitoring theory; and the integrated conflict monitoringreinforcement learning theory is close to defining the role of basal ganglia in the EMPS. The
hypothesis of alcohol-related glucose-dependent system of error monitoring & processing
(ARGD-EMPS Hypothesis) suggests a mechanism of alcohols effect on the EMPS (Welcome
et al., 2010).
5.1. The reinforcement learning theory

One of the integral properties of the basal ganglia is to determine whether the end-result of
events will be favorable or not; and is crucial to the functioning of EMPS. The basal ganglia
monitor and steadily predict the result of ongoing events (Welcome et al., 2010; Botvinick et
al., 2001 & 2004; Holroyd & Yeung 2003; Garavan et al., 2002; Gehring et al., 1993 & 2001).
The basal ganglia is one of the many brain structures that send command information to the
ACC for further processing (it is presently not clear the kind of information that might
require further processing in ACC, or whether these processes only represent one of the
many brain mechanisms for safety) (Holroyd & Coles 2002; Holroyd & Yeung 2003;
Welcome et al., 2010). It is however, possible that these command information are too
complex for only the basal ganglia to process, hence need other more specialized locations.
That is why the ACC functions as a selector for conflicted command. This is why the ACC is
regarded as a control filter (Welcome et al., 2010; Carter et al., 1998; Nieuwenhuis et al.,
2003; Ridderinkhof et al., 2003). The major neuromediator here is dopamine. Its tonic
activity depends on reinforcing properties of alcohol (Holroyd & Yeung 2003; Munte et al.,
2008; Montague et al., 1996). Alcohol may increase the tonic activity of dopamine system
and subsequently leading to inhibition of neuronal activity, the result is increased error
commission (Welcome et al., 2010; Holroyd & Yeung 2003; Easdon et al., 2005).
5.2. The conflict-monitoring theory

Although there are less information as regards to this theory with respect to the basal
ganglia. Research suggests that the basal ganglia may be actively engaged with other
systems to monitor conflict (through the sub-cortical pathways). This is an important aspect
of information processing for cognitive control (Botvinick et al., 2001 & 2004; Welcome et al.,
2010; Gehring et al., 2001). Conflict occurs as a result of simultaneous activation of different
regions, controlling the activation of different levels of competing motor control units in the
motor cortex. Processing of stimulus is characterized by constant flow of activity in the
pathways that send stimulus related information to the cortex of the hindbrain, and
subsequently results in the corresponding response in the motor cortex (Botvinick et al.,
2001 & 2004; Welcome et al., 2010). Distractive stimulus may activate incorrect response in
this system (Goldstein et al., 2007; Holroyd & Coles 2002). Alcohol related disruption of
information processing decreases the activation of correct responses (through its inhibitory
effect) (Holroyd & Yeung 2003). In addition to the dopamine system (Holroyd & Coles
2002), GABA and glycine might also play a role (Wick et al., 1998).

5.3. Integrated conflict monitoring-reinforcement learning theory

In view of this theory, although not fully clear, the basal ganglia generate error signals (i.e.
the basal ganglia undertake processing of input signals, and are end-result predictors).
Hence, the basal ganglia have been referred to as adaptive critics. It is also possible that the
error signals processed in the basal ganglia are received from ACC (Ridderinkhof et al.,
2003; Umhau et al., 2003). Sometimes, however, end-result can be different from the input
signal (especially when result was not predicted). The resultant effect is a shift in dopamine
signal. The error produced is called temporal difference error. These errors are sent through
the dopamine system to other brain regions for further analysis: a) motor control systems
(such as dorsolateral prefrontal cortex, amygdala); b) control filter (ACC); c) and again to the
basal ganglia. These processes suggest that the basal ganglia are some of the chief brain
error processors that ensure adequate completion of information processing for cognitive
control. A disruption in dopamine signal caused by alcohol in these brain regions disinhibits
adequate processing of information (Nieuwenhuis et al., 2003; Ridderinkhof et al., 2003;
Umhau et al., 2003; Holroyd & Yeung 2003; Holroyd & Coles 2002; Hester et al., 2005;
Garavan et al., 2002; Easdon et al., 2005).
6. Mechanism & processes of alcohols effect on the error monitoring and

processing functions of the Basal Ganglia: The ARGD-EMPS hypothesis
revisited and redefined
How does alcohol exert its action on the error monitoring and processing capacity of the
basal ganglia? This is a question that is virtually left unanswered as the traditional theories
of error processing do not provide suitable answers. Of all the theories of error monitoring
and processing, only the hypothesis of alcohol-related glucose-dependent system of error
monitoring & processing (ARGD-EMPS hypothesis) gives a somewhat precise definition of
how alcohol affects the EMPS, although, even ARGD-EMPS hypothesis has its shortcomings. For one reason, while ARGD-EMPS hypothesis proposes an indirect mechanism of
alcohols action on the EMPS, a direct pathway is also possible. Secondly, the hypothesis
considers competency of glucose homeostasis regulation to affect the ACC primarily, and
then, consequently, affecting other components of the system. Finally, the effect of alcohol
on the EMPS might take a much longer time than expected.
The ARGD-EMPS hypothesis which explains the general processes and mechanisms of
alcohol-related disruption of the EMPS, suggests that the disruption of EMPS by alcohol
might be indirect and realized through its effect on the competency of glucose homeostasis
regulation (Welcome et al., 2010) (also see Fig. 2). The major postulates of this hypothesis
hold that the error processing capacity of the ACC depends on the blood-brain glucose
proportionality level, which affects the dopaminergic system as a major component of the
EMPS (Pizzagalli et al., 2003; Umhau et al., 2003; Goldstein et al., 2007).
From figure 2, one can notice that one of the central dogma of the ARGD-EMPS hypothesis
is the degree of glucose homeostasis (allostasis is a better terminology) regulation in blood
Significance level: *in relation to the initial level; OOin relation to the parameters of the opposite group.
References to figure: Welcome et al., 2010 & 2011; Krebs 1968; Nieuwenhuis et al., 2004; Ridderinkhof et al., 2002;
Holroyd & Yeung 2003; Montague et al., 1996; Carter et al., 1998; Bello & Hajnal 2006; Haltia et al., 2007; Williams et al.,
2007; de Galan et al., 2006; Calhoun et al., 2004; Umhau et al., 2003; Haight & Keatinge 1973; Krebs et al., 1969; Wick et
al. 1998
Figure 2. Ethanol affects the functions of the EMPS by altering the brain and blood glucose levels
through its action on the mechanisms (gluconeogentic etc) that regulate the blood-brain glucose
concentration (the effect is also evident among sober individual, even for 10-30 days after alcohol use.
Genetic variations in dopamine, GABA receptors can also affect the activities of the EMPS. The resultant
effects of all these components on EMPS indirectly affect cognition, at the same time as the level of
cognition can affect the activity level of EMPS. Ethanol as a component of environmental factors can
affect cognition. Ethanol reduces the glycemic level of alcohol users, especially in tasks requiring high
cognitive control, and subsequently affecting EMPS.
and brain. Disorder in glucose homeostasis regulation in blood, and in the brain, especially
under long-term intensive mental activities in alcohol users is the basis for the formulation
of the ARGD-EMPS hypothesis. Importantly, road traffic, and aviation catastrophes, glucose

allostasis regulation might stand out to be a major reason. Unarguably, long-hour driving
and airplane control requires significant cognitive control, judgment. In alcohol users (even
after 7-30 days of alcohol use), this cognitive control might malfunction by increase in error
commission, especially after long period (~4 hrs and above) of driving or control. The
situation might be pronounced for young people. Besides, catastrophic cases of vehicle
accidents involving alcohol use are more prevalent among young people, especially among
students (Del Rio Carmen et al., 2001). While alcohols time-dose effects are largely studied,
data about the time-response effect in healthy young individuals remain scanty. In our
recent work (Welcome et al., 2011), for the first time, we were able to identify statistically, a
lowering of glycemic allostasis regulation in young sober healthy students who use alcohol
episodically in moderate doses. This lowering in glycemia correlated significantly with
cognitive functions. The study was conducted after one week to a month abstinence period
for alcohol users to extensively study the time-response effect of alcohol.
6.1. Relationship between alcohol use and cognitive functions

In the study (Welcome et al., 2011; tables 1, 2, and 3), analysis of the parameters of
effectiveness of active attention (a function of cognitive control) in the participants was
conducted according the results of the test Correction Probe and was based on the
number of error commission in the test. Number of error commission by the episodic
alcohol users in the test Correction Probe was by 5.43 (<0.02) 12.77 (<0.005) times
higher compared to the non-alcohol users in all phases (tests) of the experiment (table 1).
Number of error commission by alcohol episodic alcohol users significantly exceeded in all
phases of mental activities (after 2, 4 and 6 hrs) and was after 6 hrs from the start +17.65.8
errors (<0.01), or 218.4 % in relation to the initial number (table 1). Among the non-alcohol
users, the number of errors did not change and remained low and stable during the
experiment.
The number of errors in the test Correction Probe also allowed to analyze a very
important property of active attention concentration which is the possibility to focus on
ongoing activities so as to minimize error commission to 5 errors in the test Correction
Probe. This property of attention was especially expressed among the non-alcohol users (in
87.5 100.0% cases), both in the initial (1st) test and in course (dynamics) of carrying out
mental activities (table 1). Among alcohol users attention concentration or focus was
retained only in 4 (>5 errors in the test Correction Probe) out of 19 persons. As a result of
this, the estimated relative probability of maintaining proper attention concentration or
focus ( 5 errors in the test Correction Probe) among non-alcohol users was 4.15 times
(<0.002; 2=10.296) higher, than among their colleagues who use alcohol. According to the
measure of carrying out mental activities, concentration of attention among the alcohol users
decreased and remained low even after two hrs of rest. As a result, the risk of error
commission of more than 5 in the test Correction Probe and lowering of the concentration
of attention among the alcohol users increased from 6.29 to 8.00 (<0.001; 2=17.459) times
compared to the non-alcohol users.
Test number and time of carrying

out the test
1st, initial (M m),
,t at df=7 to the parameters of
1
2nd, after 2hrs of work (Mm)
, t * - to the initial value of its own
group
,t at df=7 to the initial value of
1
3rd, after 4hrs of work (Mm)
, t * - to the initial value of its own
group
,t at df=7 to the value of 1
4th, after 6hrs of work (Mm)
, t *- to the initial value of its own
group
5th, after 2 hrs of rest (Mm)
Number of errors in the test CP Dynamics of number of errors

group 1
group 2
group 1
group 2
2.8 0.8
15.2 3.5
---
---
+ 3.0 1.4 *
<0.05;t=2.143;
df=18
<0.02; t=3.471
2.4 0.7
18.2 4.1
0,4 0,5
>0.05
>0.05
>0.05
<0.01; t=3.847
3.1 0.7
>0.05
2.6 0.7
>0.05
2.5 1.1
25.1 4.9
>0.05
<0.005; t=4.477
33.2 7.1 *
<0.05;t=2.288;
df=17
<0.005; t=4.315
23.3 4.2
<0.005; t=4.755
>0.05; t=2.272
+ 0.3 0.8
>0.05
0.2 0.6
>0.05
0.3 0.9
+ 9.0 3.5*
<0.02;t=2.586;
df=17
<0.05; t=2.415
+17.65.8*
<0.01;t=3.034;
df=17
<0.02; t=3.052
+ 13.2 6.9
>0.05
Note: group 1 non-alcohol users (8 persons); group 2 alcohol users (19 persons). Significance of differences
was calculated with Students t-test: * significance of the differences in relation to the parameters of students in its
own group on the first test (initial parameters in its own group); significance of the differences in relation to
analogical parameters of non-alcohol users in the same phase (number) of testing.
Table 1. Number of errors and effectiveness of attention in the test Correction Probe (CP)
These facts strongly suggest that alcohol use, even episodic in moderate doses leads to longterm (1 4 weeks) negative effect on the state of cognitive functions in sober young people.
This is manifested through decrease in the concentration of attention and worsening of the
processes of active attention (table 1), processes of thinking, different types of memory
resulting in inability to preserve proper level of mental performance for a long period of
time and relative rise of fatigue. In addition, analysis of academic performance (which might
represent a factor of cognitive functions) show decrease in the effectiveness to sit for
examinations only among the alcohol users.
6.2. Episodic alcohol use, glycemia and cognitive functions: What are the
possible connections?
Research data on the chief role of glucose in energy supply for neurons and the inhibition of
gluconeogenesis during acute or chronic alcohol poisoning have been repeatedly reported
(Krebs 1968; Krebs et al., 1969; Goodlett & Horn 2001). The result of our study suggests that
that inhibition of gluconeogenesis by ethanol is fairly long process (1 4 weeks, and may
possibly last longer until complete recovery of gluconeogenetic enzymes by de novo
synthesis).

Blood sampling
Initial, before work

t , St. to abstainers
group 1
After 2hrs of work
* t , St. to the initial
t ,St. to 1
Dynamics to initial
t ,St. to 1
After 4hrs of work
t ,St. to 1
Dynamics to initial
t ,St. to 1
After 6hrs of work
* t , St. to initial
t ,St. to 1
Dynamics to initial
t ,St. to 1
Concentration of glucose in capillary blood (Mm), mmol/l

All participants, n=27
Non-alcohol users,
group 1, n=8
Alcohol users,
group 2, n=19
4.45 0.12
4.24 0.19
4.54 0.15
> 0.05
4.850.10 *
<0.02;t=2.548;df=26
> 0.05
+0.400.08 *
<0.001;t=5.000;df=26
<0.05;t=2.385;df=7
4.790.12n=26
>0.05;t=2.000;df=25
<0.05;t=2.385;df=7
+0.350.15 *
<0.05;t=2.333;df=25
<0.01;t=3.568;df=7
4.540.21n=26
>0.05;t=0.372;df=25
<0.005;t=5.020;df=7
+0.100.25
>0.05;t=0.400;df=25
<0.005;t=4.848;df=7
> 0.05
4.910.15 *
<0.05;t=2.792;df=7
+0.670.08 *
<0.001;t=8.375;df=7
5.400.18 *
<0.005;t=4.462;df=7
+1.160.17 *
<0.001;t=6.824;df=7
5.780.13 *
<0.001;t=6.696;df=7
+1.540.16 *
<0.001;t=9.625;df=7
4.820.13
>0.05;t=1.914;df=18
> 0.05
+0.280.10*
<0.02;t=2.800;df=18
<0.02;t=3.042;df=7
4.520.11n=18
>0.05;t=0.091;df=17
<0.005;t=4.190;df=7
0.010.14n=18
>0.05;t=0.007;df=17
<0.002;t=5.294;df=7
3.990.18n=18
<0.05;t=2.347;df=17
<0.001;t=8.063;df=7
0.550.24 *n=18
<0.05;t=2.292;df=17
<0.001;t=7.232;df=7
Note: * differences are significant in relation to the initial level of glycemia in its own group before work (the first
blood sampling) with respect to Students t criterion (St.). differences are significant in relation to the level of
glycemia among the non-alcohol users on the same phase of blood sampling. n number of participants in the group.
Table 2. Initial parameters and dynamics of blood glucose in capillary blood of all respondents in a
condition of long-term, intensive mental activities
Inadequate level of glycemia for long-term energy supply for actively working neurons,
which is accompanied by lowering of their activities and subsequently a decline in cognitive
function, even in sober respondents could be due to inadequacy in the activity of
gluconeogenetic enzymes. The observed disorders in glucose metabolism may be expressed
in conditions of intense functional workloads, for example, mental activities, imposed on
sober respondents on fasting in the catabolic phase of metabolism. This assumption is
confirmed by the result of studying the dynamics of glucose in the blood of hungry people
with different attitudes to alcohol in a condition of long-term functional workload (on
fasting) in the form of intensive 6 hrs mental activities (table 2).
The results of this study showed increase in the level of blood glucose in all 27 participants
in the first 2 hrs of mental activities (figure 2; table 2) by +0.40 mmol/l (<0.001): among the
non-alcohol users +0.67 mmol/l (<0.001), in the sober respondents +0.28 mmol/l
(<0.02). Further dynamics of glycemic level in the remaining 26 participants (one
participant declined from continuing the experiment as a result of fatigue after 3hrs from the
start), that continued the experiment was different from that in the first two hours of work.
Increase in the level of glycemia after 4 hrs of mental work was +0.35 mmol/l (<0.05)
compared to the initial level; by 0.05 mmol/l less compared to the level after 2hrs (table 2).
After 6hrs of mental work average glycemic level increased slightly, but was not different from
the level at the first blood sampling, although was less compared to the level after 2 and 4hrs
of work (table 2). This suggests that the process of using glucose is more pronounced than the
process of its formation (after 4hrs of work) and entrance of glucose into blood: the exhaustion
of reserves and stimulation of gluconeogenesis for the maintenance of proper level of blood
glucose, to providing the energy requirements of actively working cells and organs. Cessation
of increase of glycemic level after 4hrs of work among the majority of respondents and its
normalization after 6hrs of mental activities was because of the differences in the dynamics of
this important parameter in all participants (figure 2; table 2).
In all non-alcohol users, in all phases of the experiment, there was increase in the glycemic
level. The average increase of the glycemic level in relation to the initial level was +0.67
mmol/l (<0.05) after 2 hrs, +1.16 mmol/l (<0.001) after 4hrs, and +1.54 mmol/l (<0.001)
after 6hrs. Positive dynamics of increase in the glycemic level among the non-alcohol users
in a condition of active use of glucose by the brain imply a high reserve of gluconeogenesis
amongst them and its intense stimulation in a condition of long-term mental activities. If one
should bring into mind the fact that [in condition of catabolism, gluconeogenesis determines
the quantity of glucose that enters the blood (De Galan et al., 2006; Krebs 1968), and that
glucose use by the brain during mental activities increases at least by 12% (Madsen et al.,
1995; Di Nuzzo et al., 2009), that increase in glycemic level after 6hrs of work among the
non-alcohol users was 36.3% /table 2/], then calculation of shows increase in the activity of
gluconeogenesis by approximately 1.53 times in relation to the initial level.
Amongst the group 2 students, dynamics of glycemia after 4 and 6 hrs of mental activities
were significantly different from that of the non-alcohol users (table 2). So, increase in blood
glucose in the sober respondents after 2 hrs of mental work (+0.28 mmol/l /<0.02/) was
replaced by a decrease after 4 hrs of mental work and the development of hypoglycemia
(3.99 mmol/l /<0.05/) for capillary blood (table 2) after 6hrs of mental activities. Three
students had neuroglycopenia at the end of the experiment, because their blood glucose
level was less than 3.0 mmol/l. This is a confirmation that the reserve of gluconeogenesis in
sober individuals is significantly decreased compared to the non-alcohol users.
Pearson linear correlation analysis showed the presence of significant (linear, positive)
linkages between the glycemic level and effectiveness of cognitive function in all tests after
4 and 6 hrs of mental activities (table 3). In addition, after 4 and 6 hrs of work, there was a
significant negative correlation between blood glucose and number of error commission in
the test Correction Probe (table 3). Calculation of the coefficient of determination (r 2)
shows that the proportion by contribution of glycemic level and effectiveness of cognitive
functions in all tests were 11.8% (<0.05) after 4hrs and 15.6% (<0.05) after 6hrs of work.
The calculated percentage of the effect of blood glucose on the parameters of mental
performance clearly does not agree with literature data (Madsen et al., 1995; Di Nuzzo et al.,
2009) on the positive effect of glycemia as energy source for neurons (on the average ~ 35%).
One can assume that the effect of glycemic control on cognitive functions carry a linear

character, not a curvilinear one, especially if we consider the fact that indirect source of
glucose to the majority of neurons is through glial cells.
6.3. Effect of glycemic control on error commission

The conducted calculation of the coefficient of correlational relationship of Pearson for
the analysis of the degree of curvilinear linkage showed the presence of one-sided effect
(with average strength) of glycemia on effectiveness of cognitive function and number of
error commission in the test Correction Probe for the analysis of mental performance and
fatigue in the participants (table 3). Calculations of the coefficient of determination 2, or r2
confirms with sufficient evidence of a direct role of glycemic level (26.0% on fasting at rest;
30.0 36.7% on fasting during mental work) amongst all factors, contributing to mental
performance and the state of cognitive functions. The proportion by contribution of
glycemia (26.0 36.7 % /<0.01/) in the provision of brain functions (mental performance of
a person) closely agree with the value (35.0 %) (Madsen et al., 1995; Di Nuzzo et al., 2009) for
the provision of energy for neurons in different conditions. Therefore, sufficient
concentration of blood glucose is one of the major factors of high mental performance and
high state of cognitive processes.
Type of correlation,
pair of correlating
parameters
Values of correlation coefficients
Before work
Initial (1st)
After 2hrs (2nd)
Participants
n=27
n=27
rPearsonGl NO in the
r = 0.01
r = 0.165
test CP,
= 0.994
= 0.206
Pearson Gl NO in
= 0.510
= 0.548
the test CP,
< 0.001
< 0.01
Effect of Gl on NO 2100% = 26.0% 2100% = 30.0%
During work
After 4hrs (3rd)
n=26
r = 0.364
= 0.034
= 0.606
< 0.001
2100%=36.7%
After 6hrs (4th)

n=26
r = 0.398
= 0.022
= 0.556
< 0.001
2100%=30.9%
Note: Gl glucose (concentration of glucose in capillary blood); NO number of errors; test CP test Correction
Probe; r linear correlation coefficient of Pearson; curvilinear correlation coefficient of Pearson; significance
of linkage between the parameters with respect to r linear correlation coefficient of Pearson set at 0,05;
significance of one-sided effect of glucose on number of error committed by the participants on the test CP, in
relation to curvilinear correlation coefficient of Pearson set at 0,05. Proportion of interrelationship of the
analyzed parameters were calculated based on the coefficient of determination (r2) [see Welcome et al., 2011]. Tests
were conducted together with the blood sampling of glucose in each phase of the experiment.
Table 3. Effect of glycemia on the parameters of cognitive functions and the functional state of the
participants
The hypoglycemic effect of acute alcohol administration has been known for decades. As
reported by Hans Krebs and associates, alcohol reduces the activeness of gluconeogenetic
enzymes (Krebs 1968; Krebs et al., 1969). We had reported that the negative effect of chronic
(episodic) alcohol use on gluconeogenesis maybe long-term (might last even for 10-30 days
after alcohol use), and might be noticed under long-term mental work (4-6 hrs), especially in
task requiring high cognitive control (Welcome et al., 2011; Fig. 2).
The fact that decrease in neuronal gluconeogenesis (leading to blood-brain glucose level)
caused by alcohol consumption in a cognitive task might affect the activities of the EMPS by
increase in the number of error commission is evident in the hypothalamic control of blood
and brain glucose levels (Welcome et al., 2010; Volkow et al., 2006). The blood glucose level
increases with increase in dopamine level on fasting (Umhau et al., 2003). Effect of glucose
on dopamine is realized through the activities of GLUT- 2 receptor located in hypothalamic
neurons (Umhau et al., 2003; Williams et al., 2007; Pizzagalli 2003).
The basal ganglia and hypothalamus are actively engaged with the brain regions of
cognitive control to adequately carryout a task to meet set aims. To meet the set aims, one of
the control mechanisms is to avoid error commission. However, in rare circumstances error
commission can be an adaptive mechanism for safety, and accommodation, and may result
from neuronal selectivity pattern (Gehring et al., 1993; Hester et al., 2005; Bello & Hajnal
2006). The increased error commission associated with alcohol consumption is related to
decrease in dopaminergic functions (Nieuwenhuis et al., 2002; Holroyd & Yeung 2003),
which is caused by decreased competence of glucose allostasis regulation (Welcome et al.,
2010, 2011).
It is possible to assume that functional hypoglycemia among sober individuals (within a
period of 30 days after alcohol use) in a condition of mental activities may lead to disorders
in dopamine metabolism and subsequently cause disruption of EMPS through increase in
erroneous actions.
According to the ARGD-EMPS hypothesis, the disruption of the EMPS is related to the
competency of glucose allostasis regulation, which in turn may determine the dopamine
level as a major component of the EMPS (Welcome et al., 2010).
Blood and brain glucose levels play a vital role in error commission, and are related to error
commission, monitoring and processing through the modulation of the activity of the
dopaminergic system (Volkow et al., 2006; Umhau et al., 2003; Williams et al., 2007;
Pizzagalli 2003). In fact, decreased glucose metabolism in ACC closely correlates with the
results of neurophysiological tests (Pizzagalli et al., 2003).
The ARGD-EMPS hypothesis was put forward based on recent evidences, which suggest
that alcohols action on error monitoring ad processing is related to its action on glucose
homeostasis regulation, especially in tasks requiring high cognitive control (Welcome et al.,
2010). In addition, the number of errors committed in an experiment is inversely correlated
with the glycemic levels, especially among alcohol users (Welcome et al., 2010, 2011; Fig. 2).
In addition, correlation analysis between academic performance and the number of errors
committed by alcohol users in high-level cognitive task is also a confirmation (Welcome et
al., 2010, 2011; Fig. 2).
7. Conclusion
The basal ganglia represent a crucial relay station for error monitoring and processing
between several brain regions including emotional and cognitive brain areas. The disruption

of error monitoring and processing by alcohol might not follow an indirect pathway only,
but also a direct one. Indirect effect of alcohol may be possible through the processing
capacity of the basal ganglia by affecting other brain areas connected to the basal ganglia;
action of alcohol metabolites (acetaldehyde; acetate; protein-, lipid-, enzyme-, and DNAadducts of alcohol) on the processing of information in the basal ganglia and/or associated
brain pathways; and its action on neuromediators that modulate the processing of
information in the basal ganglia and/or associated brain pathways. The direct effect might
be attained if alcohol reach the basal ganglia and causes disruption of cellular processes
including information processing. The effect is a change in effectiveness of cognitive
functions, error commission in the macro world. The effect of alcohol on the basal ganglias
error monitoring and processing capacity might last for several days after alcohol use (up to
30 days). This effect might be noted, especially under long-term intensive mental activities
requiring high cognitive control, when the glucose reserves in the body cannot support
long-term actively working neurons, and this may lead to disorders in dopamine
metabolism and subsequently cause disruption of EMPS through decrease in effectiveness
of cognitive functions, increase in erroneous actions.
8. Future research
Future research will examine both the electrophysiological (ECG, ERN etc.) and radiological
(PET, etc) parameters of dose-time response effect of alcohol in details. In the initial stage,
animal models will be used to research the basis and to test how alcohol affect specific
neuron or group of neurons in basal ganglia-thalamo-cortico-limbic pathways. Other
pathways with indirect connections to the basal ganglia whose dysfunctions may necessary
lead to a decrease in basal ganglia function will also be examined. A knockout of the alcohol
pocket-receptor might also reveal useful information about the indirect effect of alcohol on
error monitoring and processing.
Author details
Belarusian State Medical University, Minsk, Belarus
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Chapter 4
The Integrative Role of the Basal Ganglia

Clemens C.C. Bauer, Erick H. Pasaye,
Juan I. Romero-Romo and Fernando A. Barrios
http://dx.doi.org/10.5772/54189
1. Introduction
Emergent experimental and clinical evidence supports the notion that the cortico-basal
gangliathalamo-cortical loops progress along parallel circuits connecting cortical and
subcortical regions subserving the processing of sensorimotor information, associative and
affective knowledge [1]. In particular the role of the basal ganglia has long been known to be
involved in motor control because of the marked deficits associated with their damage.
However, the exact aspects of motor control that they have under normal conditions have
not been clear at all. The traditional view is that the basal ganglia are involved in the
selection and inhibition of action commands [2], but an increasing number of brain-imaging
studies show that the basal ganglia, besides being involved in motor tasks are also involved
in more integrative and cognitive processes such as mental imagery [3,4], sensory
processing [5,6], planning [7], attention [8,9], and language [6,10,11]. This evidence supports
the view that the basal ganglia output not only targets the primary sensory-motor cortices,
but also specific areas of premotor and prefrontal cortex, which include the oculomotor area
of the cortex, the dorsolateral prefrontal cortex, lateral orbitofrontal cortex, and anterior
cingulate/medial orbitofrontal cortices [12]. Thus, having the ability to influence not only
sensory-motor control, but also several different types of cognitive and limbic affective
functions [12] which underlie complex and integrative processes such as self-awareness,
introspective perspective of ones own self and consciousness [13]. This integrative role
between lower afferent input and higher integrative and executive stages of information
processing require an intact and closed loop of information flow to generate the primary
experience of self and thus self-agency. Self-agency has tentatively been defined as the
feeling of being the author of ones own actions [14]. Thus, when we move our arm, we
know (a) that it is our arm and (b) that it is us, who moves the arm. One approach to
understand the complex integration of afferent and efferent information processing and the
integration in the self is the internal model theory of motor control [15]. According to this
theory there are two functionally different components in the motor system, inverse and
2012 Bauer et al., licensee InTech. This is an open access chapter distributed under the terms of the
forward circuits. It is assumed that inverse models provide the motor commands necessary
to achieve a desired consequence of an action, specified by higher-level goals (e.g.,
intentions). One is fully aware of the desired consequences of an action, but unaware of the
motor programs per se. Forward models predict the sensory consequences of each motor
program to be executed, an idea known as the efference copy, a model first put forward in
von Holst and Mittelstaedt [16] and which has been extended in recent years with the null
hypothesis of Ramachandran [17]. Accordingly, it is claimed that, whenever a motor
program is issued, an efference copy is produced in parallel, this is, a prediction of the
sensory consequences expected after the execution of the program based on exactly this
efference copy. The internal model theory of motor control has been successfully applied to
explain a whole variety of disorders related to the awareness of actions [for a review see 17]
but the role played by the basal ganglia in this model has not been very clear. Here we
follow this model extending it to the performance of a complex cognitive task, such as
mental imaginary movement of a limb and the coexistent conscious awareness of just
imagining it and actually refraining from moving it which involves exactly this subtle
combination between the forward model requiring intact peripheral efferent/afferent
information pathways and the inverse model requiring intact higher-level cortical areas
which include the basal ganglia-thalamus-cortex pathway [19]. Moreover, we contrast the
normal integrity of this forward/inverse model loop in healthy subjects with an abnormal
open loop in amputees where an essential part of the loop has been disrupted. We thus
argue that because of this abnormal and open loop involving the basal ganglia and the
thalamocortical system the conscious awareness of the phantom phenomenon is created.
2. Problem statement
Waking up from anesthesia, an amputee faces the conflict in the experience of self, between
the conscious vividness of his phantom limb (PL) and the lack of correlation with reality
[2023]. In the urge to discover whether he was actually amputated, the patient looks under
the sheet for visual self-recognition and is, in a flash, confronted with this new reality of an
absent limb. The resulting cognitive conflict between the seen embodiment and the felt one,
in most cases carries on resulting in the perception of a ghost of their amputated limb as a
phantom [24]. Giummarra et al. [20] report phantom limb experiences that include
phenomena of (a) perception of bodily aspects of phantom limbs such as size (in relation to
the intact limb), shape, posture, and telescoping (or shortening) of the phantom; (b)
exteroceptive and proprioceptive sensations and (c) prosthesis embodiment. Early studies of
phantom limb movement were carried out using combined techniques of EEG, MEG, and
fMRI in order to locate its representation in the sensory-motor cortex [2528] and in the
cerebellum [29,30]. Later studies described the distinct functional anatomy of the mental
representation of imaginary movements [31], during planning, visualizing, and motor
intention [32], both in healthy subjects as well as in patients with different neural diseases.
Other studies have centered on the difference between imaginary movement and executed
movement [3,33]. A recent study by Diers et al. [34] showed activation in the supplementary
motor area (SMA) cortex after PL imagined movement. And in a more recent study Pasaye
et al. [35] have described nuerocorrelates of the PL perception using fMRI. Since the first
conceptualization of the phenomenon of phantom limb in amputees in 1915, as the

manifestation of the persistence of the body schema of the missing limb [36], many theories
have arisen. Most of these theories suggest a central role of reorganization of the
somatosensory cortex, others advocate for a perceptual completion [37], or the product of
conflicting cues from central reorganizational changes [38]. Although some degree of
sensory or motor impairment is constant, recent models of motor awareness suggest that the
reduction in afferent information may be less critical than higher-level reorganization related
to the subjective correlates of action planning and motor intention [15,39]. In contras, a
number of studies of patients with amputated limbs encourage that a conscious perception
of a body part by tactile stimulation does not necessarily require the integrity or even
existence of the tactile receptors on the skin, or the body parts themselves. That is, the neural
representation of the body in the brain is sufficient to elicit an awareness of the body part or
tactile stimuli in the absence of its physical counterpart (e.g., the limbs themselves) [40]. We
believe that the reduction or absence in afferent information is a key factor that in
combination with higher-level reorganization generates the conscious awareness of the
phantom phenomenon. Here we hypothesize that for the performance of a complex
cognitive task, such as imaginary movement of a limb, and the concomitant conscious
awareness of just imagining it and actually refraining from moving it, an involvement of a
subtle combination between intact peripheric (efferent/afferent) information pathways and
intact higher-level cortical areas (basal-ganglia-thalamus-cortex pathway) are needed [19].
In amputees, this normal combination of lower- and higher-level processes is disrupted and
could be the underlying cause of conscious awareness of the phantom limb. This
arrangement of processes was reported by Staub et al. [41], who found an increased blood
oxygen level dependent (BOLD) signal in the Basal Ganglia-Thalamic-Motor-Cortex loop
pathway during imaginary movement of a patient with chronic supernumerary phantom
limb, which developed only in association with motor intent directed at a hemiplegicanesthetic upper limb. Staubs finding is analogical to what Ramachandran proposes as the
null signal hypothesis in the mirror neuron system (MNS), which prevents activity in the
MNS from reaching the threshold for conscious awareness [17] or related to what Fitzgibbon et
al. [42] suggests as the underlying cause in synesthesia for pain. We think that the logic behind
Ramachandrans hypothesis is plausible, and if applied to an intact afferent somatosensoryproprioceptive and efferent motor feedback, no activity in the basal-ganglia-thalamus-cortex
loop would be seen in healthy subjects, in contrast to the incomplete closing of the
afferent/efferent loop and therefore an absence of the null signal in the case of amputees.
Hence the inhibition of activity in the basal ganglia-thalamus-cortex pathway is disrupted,
thereby generating an abnormal open loop functioning of the thalamocortical system and its
consequent activation. This abnormal activation of the thalamocortical system, we suggest,
could be the underlying cause of the conscious awareness of the phantom phenomenon.
This hypothesis is also in accordance with an emergent change of view in the functionality of
the basal ganglia, from the classic view of being just part of the common motor pathway, to a
more integrative, dynamic and resource-selection mechanism that participates in the sensorymotor, affective, and cognitive process related to the executive planning and selection of an
action mechanism [43]. Furthermore, the conscious awareness and the subsequent sense of
agency [44] which patients report to have had as they perform imagined tasks with their
amputated limbs has never between contrasted with healthy subjects.
In the current study, we tested the hypothesis that the basal ganglia-thalamus-cortex
pathway is disrupted in amputees, as compared to control subjects, and that this disruption
is the key to the cascade of conscious awareness of the phantom limb. We contrasted
between lower limb amputees and control subjects as they performed a simulated
neurocognitive motor-imagery task with their phantom toes or intact toes respectively.
3. Method used
3.1. Subjects
Six unilateral lower limb amputees, 3 with left lower limb (LLL) and 3 with right lower limb
(RLL) amputation (mean age 35.3, range 15-60 years, for details see Table 1), and 6 healthy
controls (HC, mean age 29.16, range 20-59 years) participated in the study. All participants
gave written informed consent prior to taking part in the study and the local institutional
review board approved the protocol, which adhered to the Declaration of Helsinki. None of
the subjects had neurological or psychiatric disorders.
Age1
Ctrl
Age2
Pat
Amp3
side
Amp4
site
Cause of5
Amputation
SP6
PLP7
PLS8
20
34&
RLL
TF
Traumatic
21
15
RLL
TT
Traumatic
22
44
RLL
TT
Traumatic
24
60
LLL
TT
Traumatic
29
33
LLL
TF
Traumatic
59
26
LLL
TT
Traumatic
Table 1. Clinical data description of controls and patients. All subjects are right handed males. 1Column
for control subjects age. 2Column for patients age. 3Three patients had right lower limb amputation
and three had left lower limb amputation.4Site of surgery. 5Car or train accident was main cause of
amputation. 6All the patients reported stump pain (SP), but 7none ever had Phantom Limb Pain (PLP).
8All patients were able to move at will their phantom toes (extension/flexion).
3.2. Experimental procedure

The experiment consisted of two parts. In the executed movement condition the participants
were instructed to make a flexion/extension movement with the intact (amputees) or nondominant (HC) toes. In the condition imagined movements the amputees imagined making a
flexion/extension movement with the phantom toes and the HC imagined the same movement
with their dominant toes. For all conditions the subjects had their eyes open. All movements or
imagined movements were observed under close scrutiny by the researcher. All conditions
were separate blocks of fMRI measurements with durations of 30 seconds each, separated by
resting periods of 30 seconds. Each condition was repeated three times. There was no training
session for either the control subjects or the amputees.
3.3. fMRI measurement

The fMRI scans were conducted with a GE 1.5 T GE LX Magnetic Resonance instrument
(Milwaukee, WI, USA) using the standard quadrature headcoil. Subjects head was securely
fastened in the head holder to minimize movement. Functional images were acquired with
GE EPI-BOLD pulse sequence with 90 flip angle TE=60 ms, TR=3000 ms, over seven
contiguous coronal sections, 8.0 mm thick with zero gap. Imaging was centered near the
central gyrus. Structural images localized exactly over the same seven sections of the
functional studies were obtained using a high resolution T1 weighted protocol. The
activation was done in boxcar block paradigm of 30 seconds of stimulated state and 30
seconds of un-stimulated state, over a total of three blocks each.
3.4. Image analysis

All MR data was transferred to an offline workstation all images were translated into timeordered stacks using the software MRIcro (Chris Rorden, http://www.cabiatl.com/mricro/).
The experiments were analyzed subject by subject following a standard motion correction
with image registration, to do a more precise alignment, since the study was acquired in
coronal slices, the high resolution T1-weighted images were aligned to the T1-weighted
SPM mask in MNI space, the transformations were saved and applied to the functional EPI
time ordered stacks, and then the functional images were normalized to a ROI of the EPI
standard provided by SPM, spatial smoothing using a Gaussian kernel of FWHM 6mm and
high pass temporal filtering. Functional signal was obtained with a block model convolved
with an hemodynamic response function (HRF) without time derivative correction these
single subject analysis resulted in contrast maps used in the second level analysis. The
second level analysis was executed to estimate group average activation using a Studentt
maps limited and adjusted with p = 0.05 with no Volterra interactions.
4. Results
Analysis of the data was carried out for each subject individually, to see if there were
statistically significant activation clusters, and then by group after combining all subjects.
The average functional maps obtained revealed ipsilateral or contralateral brain activation
sites, which were colored according to the tasks performed on each lower limb of all
subjects: green-colored brain activation sites correspond to the right leg, while red-colored
brain activation sites correspond to the left leg. Yellow-colored sites correspond to areas of
overlapping activation during the performance of the tasks on each limb. The results of the
three groups brain activation sites are summarized in Table 2.
Talairach coordinates
BRAIN REGION
BA x
RIGHT
BRAIN REGION
Talairach
coordinates
BA x y
z
Left amputee,
executing right
imaginary motion
Middle Temporal
Gyrus
22
-61 -37 6
Paracentral Lobule 4
-10 -38 63
Medial Frontal
Gyrus
-6
Precentral Gyrus
Lentiform Nucleus, *
Putamen
Middle Temporal
Gyrus
21 51 -29
-5
-14 62
-30 -20 64
-26 -8 4
Left amputee, executing
left virtual motion
Medial Frontal
Gyrus
-8
-11 50
Medial Frontal
Gyrus
-26
64
Sub-Gyral
37
-48 -39 -5
Medial Frontal
Gyrus
-9
61
Superior Temporal 22
Gyrus
-59 -35 9
Substania Nigra
-24
-14
Thalamus
-8
Superior Temporal 21 48 -27

Gyrus
-5
Precentral Gyrus
-42 -11 47
-25 1
Right amputee,
executing left imaginary
motion
Gyrus
-65 -42 15
Gyrus
-1
Gyrus
-65 -18 -1

Gyrus
Postcentral Gyrus
-44 -17 54
Medial Frontal
Gyrus
50
Cingulate Gyrus
24
-8
Middle Frontal
Gyrus
40 -5
-10 41
Cingulate Gyrus
24 8
Thalamus
-11
-12
46
37
18 -9
13
Gyrus
-3
Right amputee,
executing right virtual
motion
Precentral Gyrus
-12 -32 62
Medial Frontal
Gyrus
-10 -26 58
Talairach coordinates
BRAIN REGION BA x
y z
Superior Temporal 42 -63 -28 14
Gyrus
Superior Temporal *
Gyrus
Precentral Gyrus
BRAIN REGION
Talairach
coordinates
BA x y
z
-63 -21 3
-50 -12 41
-16 -10 -6
Lentiform Nucleus,
Medial Globus
Pallidus
Substania Nigra
RIGHT
-8
-10 -10
Control,
executing left imaginary
motion
Inferior Frontal
Gyrus
45
-61 20 16
Medial Frontal
Gyrus
-12
71
Medial Frontal
Gyrus
-3
61
Control,
executing right
imaginary motion
Medial Frontal
Gyrus
-2
Superior Frontal
Gyrus
-8
-6 68
Medial Frontal
Gyrus
-8
Gyrus
-50 4
51
Postcentral Gyrus 43 65 -16
21
53
2
BA=Brodmann Area.
Talairach coordinates: x (left[-], right[+]); y (posterior[-], anterior[+]), z (inferior[-],
superior[+]). * no Brodmann area related
Table 2. Anatomical location of activation clusters during imaginary and virtual motion.
The average functional maps obtained from LLL amputee during the imaginary movement
of the toes of both feet also present distinct cortical and subcortical activity. Performance of
imaginary movement of the toes of the right intact toes showed activation sites bilaterally at
the STG (BA 21,22), contralateral interhemispheric M1 (BA 4), contralateral SMA (BA 6), and
contralateral Putamen. During the performance of imaginary movement with the left
amputated toes, distinct cortical and subcortical activities were observed at the following
sites: bilateral interhemispheric SMA (BA 6), bilateral STG (BA 21,22), ipsilateral M1 (BA 4),
ipsilateral Subgyral (BA 37), ipsilateral Thalamus, and contralateral Substantia Nigra
(figure 1,A).
Figure 1. Average functional activation maps during imaginary movement of the right leg (in green)
and left leg (in red) for A) left lower limb amputees, B) right lower limb amputees and C) control
subjects. All images are presented in radiological convention.
Average functional activation maps acquired from RLL amputees during the imaginary
movement of the toes of both feet depict both cortical and subcortical activities. During the
performance of imaginary movement of the toes of the left intact toes, there is bilateral
Temporal activity (BA 22), and bilateral Anterior Cingulate Cortex (ACC, BA 24), ipsilateral
Primary Somatosensory Cortex (SI, BA 3), contralateral SMA (BA 6), and contralateral
Thalamic activity, while during the performance of imaginary movement with the right
amputed toes, there is a distinct activation, namely of the bilateral STG (BA 42, 22),
contralateral Primary Motor Cortex (M1, BA 4), contralateral SMA (BA 6), contralateral
Basal Ganglia at the Medial Globus Pallidus and at the Substantia Nigra (figure 1, B).
The average functional maps obtained from the six control subjects as they performed
imaginary movement with (a) the toes of their right leg show activated contralateral sites
corresponding to interhemispheric Supplementary Motor Area (SMA, BA 6), Superior
Temporal Gyrus (STG, BA 22), and Ipsilateral Postcentral Gyrus (IPG, BA 43); while the
performance of the same tasks with (b) the toes of their left leg, activated similar
contralateral interhemispheric SMA (BA 6) and ipsilateral prefrontal (PF, BA 45) brain areas
(figure 1,C).
5. Discussion
Here we compared the brain activations of imagined and executed movements of the intact
toes and phantom toes in lower limb amputees, with the imagined and executed movement
of the toes of healthy controls, using fMRI. Both, patients and control subject expressed that
they initially had to exert greater effort in this self-generating dual process of 1) trying to
resolve an apparent conflict between the simultaneous intent to move their toes and
refraining from moving them or closing the sensory-motor feedback loop; and 2) locating,
by means of imagery monitoring, a distant portion of the body-image, which is an
attention/memory task. This sensation can be do to the increased contribution of the
prefrontal cortex, in particular the dorsolateral prefrontal cortex (DLPFC), which is known
to participate in motor imagery, not just in the sensory-motor integration and the
attention/memory neurocognitive task with the anterior cingulate cortex, but also in a joint
route with the posterior parietal cortex (PPC) during motor imagery [30,4547]. The PPC, as
a multisensory integrative cortex, plays an important role in the cognitive dynamics for
spatial representation (limb-position) and movement intent, attention, working memory,
and guidance of action [48,49]. As Jeannerod proposed If motor imagery occurred with
execution deliberately blocked or delayed, the representation would be protected from
cancellation and would become accessible to conscious processing [50]. Additionally,
controls and amputees reported that they were consciously aware of their intact toes or, in
the case of amputees, that they had the conscious perception of their phantom toes during
the imaginary task. The brain activations show similarities but also differences between
amputee groups during the imaginary movement tasks of their intact and amputated toes.
The differences were: First, both amputee groups activate Basal Ganglia areas during the
performance of the imaginary movement of the amputated toes. Second, the RLL amputee
group shows more lateralized brain activation than the LLL amputee group. Third, during
the imaginary movement task, the RLL amputee group seems to require a greater attention
control (ACC) as they performed the imaginary movement with their left intact toes than the
LLL amputee group with their right intact toes. Additionally, the brain activations observed
in the amputee group during the imagery movement task of the amputated toes involved
the Basal Ganglia loop (RLL amputee group = Lentiform Nucleus, Medial Globus Pallidus,
and Susbtantia Nigra; LLL amputee group = Thalamus and Substantia nigra). Thus, the
imagined movement task in amputees demands different circuitry subsets for its
accomplishment, namely: 1) the attention/memory/guidance loop, 2) the kinesthetic imagery
loop, and 3) the conflict intention loop. The computational logistics for such activity can
only be carried out by means of the intracortical and cortical-subcortical loops between
Thalamus and Basal Ganglia nuclei. The kinesthetic representation of an action or a planned
motor intent is the combined result of a widely distributed neuronal ensemble between
DLPFC, inferior frontal cortex, and the SMA [31], together with the posterior parietal cortex
(PPC) and the ACC for spatial awareness, attention and multisensory integration [49,51]. It
is of mayor importance to notice here that the activation of the Basal Ganglia loop was not
seen during imagery movement task of the intact toes in amputees or the healthy control
group. As far as the motor intent is concerned (Fig 1, B): a) in the control group, the
performance of the task with the left (non-dominant) toes activated contralateral SMA (BA
6) and ipsilateral inferior frontal cortex (BA 45), while the same task with the right
(dominant) toes activated contralateral SMA (BA 6), STG (BA 22), and contralateral
postcentral gyrus (BA 43). The minimal brain activity found in the controls kinesthetic
representation correlates with the ensemble proposed [52,53]. b). In the RLL amputee group,
in the coronal volumes (Fig 1, A), the performance of the imaginary motor intent with the
left intact toes activated the bilateral ACC (BA 24), STG (BA 22), ipsilateral S1 (BA 3), and
broad contralateral interhemispheric activity from SMA (BA 6) and contralateral thalamus.
However, during the right imagined movement task of the amputated toes, there is bilateral
activation at STG (BA 22/42), contralateral SMA (BA 6), M1 (BA 4), contralateral Lentiform
Nucleus (medial globus pallidus), and Substantia Nigra. The RLL amputees brain activity
for the kinesthetic representation differed between the performance of the intact imaginary
movement and the amputated imaginary movement, since Lentiform Basal Ganglia activity
is only present during the amputated toes imaginary movement. c) In the coronal-volumes
of the LLL amputee group (Fig 1, C) during the performance of the imaginary movement
task with the right intact toes, besides a bilateral MTG (BA 21/22) activation, there is clear
contralateral Lentiform Nucleus-Putamen activation, together with SMA (BA 6) and M1 (BA
4). However, during the imagery movement task with the amputated toes of the left leg,
there is an ipsilateral thalamic and a Subgyral (BA 37) activation and a contralateral
Substantia Nigra activation besides the large bilateral SMA (BA 6) and a bilateral MTG (BA
21/22) activations observed during the intact toes imaginary movement. The LLL amputee
brain activity for the kinesthetic representation differed slightly between the performance of
the imaginary movement of intact versus amputated toes, since there is Basal Ganglia
activity (Putamen) during imaginary movement of the intact toes, while during amputated
toes imagined movement there is Thalamic and Substantia Nigra activity. This Basal
Ganglia-Thalamo-Motor-Cortex loop subserves several cortex functions, such as memory
tasks, orientation in space, and the ability to change behavioral set [43,54]. In the motor
imagery task, in particular in LL amputee research literature, the role of this gangliathalamo-motor-cortex loop has never been mentioned. In this study we set out to establish
its presence using the already mentioned task in the amputee and control groups. Thus, by
comparing control and amputee groups, we found that there is minimal cortical activation
difference between them, however, the difference occurs in the subcortical activation of the
Basal Ganglia loop, since in both, the control group and during intact toes imaginary
movement of amputated subjects there is no Basal Ganglia activation, while the activation of
distinct Lenticular-Substantia-Nigra-Basal-Ganglia-Thalamic loop is clear in the amputee
group performing imaginary movement of the amputated toes. We thus propose that the
recruitment of these Basal Ganglia plays an important role in the process of conscious
awareness of a missing limb reported by amputees.
It is important to point out that we set out to find the involvement of the Basal GangliaThalamic-Motor-Cortex loop by means of this motor imagery task, as part of our hypothesis
that the amputee can and does move the phantom limbs at will, this, do to his framework of
body awareness as part of a self-related neurocognitive experience that can be as diverse as
the perceiving of size, shape, posture, itch, touch, pressure, vibration, temperature, electric
sensations and prosthesis embodiment and has been well documented [20]. Similar to
Ramachandrans null hypothesis [17] we think that the interruption of the thalamic
afferences/efferences may explain the persistence of an open loop functioning of the
thalamocortical system and its consequent activation, which is a key factor to the cascade of
conscious awareness and stability of the phantom phenomenon. This open loop functioning
of the thalamocortical system is revealed in the present study by the increased blood oxygen
level-dependent (BOLD) signal in the Basal Ganglia-Thalamic-Motor-Cortex loop pathway
during imaginary movement of the amputated toes. Thus, supporting our hypothesis of the
abnormal closed-loop functioning of the thalamocortical system as underlying the phantom
phenomenon.
6. Conclusion
To conclude, we have put forward evidence of amputee patients indirect responses to PL
experiences for an objective evaluation that suggests that the conscious awareness of a
phantom limb emerges from both the reduction in afferent information and the higher-level
brain reorganization of the cognitive representations of the amputees own body. We based
our assumptions on the hypothesis that the thalamocortical loop is closed in healthy
subjects, which enable them to distinguish an imaginary movement as actually being just
imagined. This, do to the feedback received from intact peripheric (efferent/afferent)
information pathways. The evidence shown here thus suggests that this abnormal open loop
of the basal-ganglia-thalamocortical system underlies the conscious awareness of the
phantom limb. The current approach further suggests that the basal ganglia within this
basal-ganglia-thalamocortical system loop play a crucial and complex integration of afferent
and efferent information processing. Furthermore, this integration creates the conscious
awareness of the self and is in line with the internal model theory of motor control [15]
where inverse and forward models of information processing interact continuously and
reciprocally. The inverse model component in the motor system providing the motor
commands necessary to achieve a desired consequence of an action, specified by higherlevel goals and the forward model predicting the sensory consequences of each of these
motor programs to be executed. Accordingly, whenever a motor program is issued, an
efference copy is produced in parallel and an accurate prediction of the sensory
consequences expected after the execution of the program, which in turn informs the
inverse program of the actual state of the self and closing the loop for the next command.
With this normally closed loop, the integration of the self is achieved and a normal body
ownership and awareness is crated which is necessary to create the autobiographical
experience of self.
Glossary of terms
Bottom-up: direction of information flow from the periphery (i.e. sensory cells or
mechanoreceptors) to the central nervous system.
Top-down: information flow from central nervous system toward peripheral effector cells
(i.e. muscles).
Efferent: Conveying away from the central nervous system
Afferent: Conveying towards a central nervous system
Phantom limb: is the sensation that an amputated or missing limb is still attached to the
body
Somatosensory system: sensory system composed of the receptors and processing centers to
produce the sensory modalities such as touch, temperature, proprioception (body position),
and nociception (pain).
Proprioception: sensory modality that processes the body position
Ipsilateral: same side of the body
Contralateral: other side of the body
Author details
Clemens C.C. Bauer*, Erick H. Pasaye and Fernando A. Barrios
Neurobiology Institute, Universidad Autnoma de Mxico, Quertaro, Mxico
Juan I. Romero-Romo
Quertaro General Hospital, SESEQ; Queretaro, Mexico
Acknowledgement
We want to thank Dr. Perla Salgado and Dr. Rafael Rojas form the Imaging Department of
The ABC Medical Center, Mexico City. This work was partially supported by CONACyT
R31162-A, and a Doctoral Schollarship from CONACyT Mxico and the Doctoral Program
in Biomedical Sciences in the Institute of Neurobiology, Universidad Nacional Autnoma de
*
Corresponding Author
Mxico for CCCB and EHP. We thank Leopoldo Gonzalez-Santos, Juan J. Ortiz for their
technical support.
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Chapter 5
Organization of Two CorticoBasal Ganglia Loop

Circuits That Arise from Distinct Sectors of
the Monkey Dorsal Premotor Cortex
Masahiko Takada, Eiji Hoshi, Yosuke Saga, Ken-ichi Inoue, Shigehiro Miyachi,
Nobuhiko Hatanaka, Masahiko Inase and Atsushi Nambu
http://dx.doi.org/10.5772/54822
1. Introduction
The importance of loop circuits linking the frontal cortex and the basal ganglia has
constantly been highlighted in the performance of various motor schemes [1-4]. These
corticobasal ganglia loop circuits originate from anatomically and functionally diverse
motor-related areas, which include the primary motor cortex (MI), the supplementary motor
area (SMA), and the premotor cortex (PM). Two opposing mechanisms are possible for the
processing of motor information in the corticobasal ganglia loops. One is "information
funneling" in which inputs from multiple motor-related areas are highly concentrated in
common territories of the basal ganglia. The other is "parallel processing" in which inputs
from distinct motor-related areas are topographically distributed to individual territories of
the basal ganglia. For understanding the mode of motor information processing in the basal
ganglia, it is crucial to investigate which mechanism organizes the projections from the
frontal motor-related areas to the input stations of the basal ganglia, the striatum and the
subthalamic nucleus (STN).
According to several physiological studies [5-8], it has been revealed that the caudal aspect
of the dorsal premotor cortex (F2; see [9,10]) in area 6 of macaque monkeys plays a crucial
role in the planning and execution of arm movements, and that there is certain functional
specialization between the caudal sector of F2 (F2c), located ventral to the superior
precentral dimple, and the rostral sector of F2 (F2r), located dorsal to the genu of the arcuate
sulcus. Since our prior work demonstrates that F2c and F2r receive largely segregated inputs
from the cerebellum [11], it is of great interest to explore the organization of corticobasal
ganglia loop circuits that arise from F2c and F2r.
2012 Takada et al., licensee InTech. This is an open access chapter distributed under the terms of the
In this chapter, we first summarize a series of our previous anatomical studies about the
mode of information processing in the basal ganglia based on the distribution patterns of
corticostriatal and corticosubthalamic inputs from the frontal motor-related areas of
macaque monkeys, including the PM [12-18]. The overall results indicate that the
corticostriatal and corticosubthalamic inputs from the motor-related areas are orderly
arranged according to segregation versus overlap rules. We then introduce the data of our
recent work concerning the organization of multisynaptic pathways that connect the basal
ganglia with F2. In this study, we investigated the distributions of cells of origin in the basal
ganglia of multisynaptic inputs to F2c and F2r [19]. Employing retrograde transsynaptic
transport of rabies virus, we have demonstrated that neuronal populations giving rise to the
projections to F2c and F2r are substantially segregated in the internal segment of the globus
pallidus (GPi) and the substantia nigra pars reticulata (SNr) (i.e., the output stations of the
basal ganglia), whereas intermingling rather than segregation governs for the other basal
ganglia components, involving the external segment of the globus pallidus (GPe), STN, and
the striatum (i.e., the input stations of the basal ganglia). This suggests that the loop circuits
linking F2 and the basal ganglia may possess a common convergent window at the input
stage and constitute parallel divergent channels at the output stage. The major part the
present experiments was carried out at the Tokyo Metropolitan Institute for Neuroscience,
Tokyo Metropolitan Organization for Medical Research. The experimental protocol was
approved by the Animal Care and Use Committee of the Tokyo Metropolitan Institute for
Neuroscience, and all experiments were conducted in accordance with the Guidelines for
the Care and Use of Animals (Tokyo Metropolitan Institute for Neuroscience, 2000).
2. Organization of corticostriatal and corticosubthalamic inputs

In a series of our previous anatomical studies, we have analyzed the distribution patterns of
corticostriatal and corticosubthalamic inputs from the frontal motor-related areas of macaque
monkeys [12-18]. The frontal motor-related areas that we have examined widely include the
MI, SMA, dorsal and ventral divisions of the PM (PMd and PMv), presupplementary motor
area (pre-SMA), and rostral and caudal divisions of the cingulate motor area (CMAr and
CMAc). In our studies, we initially performed intracortical microstimulation to map these
areas. Then, different anterograde tracers were injected separately into somatotopically
corresponding regions of given areas; the forelimb regions were tested except for the MI and
SMA). The overall results indicate that corticostriatal and corticosubthalamic input zones from
the frontal motor-related areas are orderly distributed in a topographical fashion, but display
complex patterns of segregation versus overlap of one another (Figs. 1, 2).
With respect to the corticostriatal inputs from the MI and SMA, dense input zones from the
MI are located predominantly in the lateral aspect of the caudal putamen, whereas those
from the SMA are in the medial aspect. On the other hand, corticostriatal inputs from the
PMd and PMv are distributed mainly in the dorsomedial sector of the putamen, although
these two input zones are virtually devoid of overlap. Thus, the corticostriatal input zones
from the MI and SMA were considerably segregated though partly overlapped in the
mediolateral central aspect of the putamen, while the corticostriatal input zones from the
Organization of Two CorticoBasal Ganglia Loop Circuits

That Arise from Distinct Sectors of the Monkey Dorsal Premotor Cortex 105
PMd and PMv largely overlap that from the SMA, but not from the MI (Fig. 1; see also
[14,15]). In addition, the corticostriatal input zone from the pre-SMA is located primarily in
the striatal cell bridges and their neighboring regions of the caudate nucleus and the
putamen, thus indicating that the corticostriatal input from the pre-SMA is spatially
separate from those from the MI, SMA, and PMd/PMv (Fig. 1; see also [17]). As for the
CMAr and CMAc, corticostriatal inputs from the CMAr and CMAc are located within the
rostral striatum, with the highest density in the striatal cell bridge region or the ventrolateral
portion of the putamen, respectively. There is no substantial overlap between these input
zones. The corticostriatal input zone from the CMAr considerably overlaps that from the
pre-SMA, while the input zone from the CMAc displays a large overlap with that from the
MI (Fig. 1; see also [16]). Moreover, it has also shown that the rostral aspect of the PMd (F7;
see [9,10]) projects predominantly to the striatal cell bridge region [18].
Figure 1. Summary diagram showing the organization of corticostriatal input zones in the putamen
that arise from the frontal motor-related areas. These input zones are orderly distributed in a
topographical fashion, but display complex patterns of segregation and overlap.
The overall pattern of corticosubthalamic input distributions is essentially the same as that
of corticostriatal input distributions. The corticosubthalamic input zones from the MI and
CMAc are located mainly within the lateral aspect of the STN, thereby leading to a large
overlap of the two input zones. On the other hand, the major input zones from the SMA,
pre-SMA, PMd, PMv, and CMAr within the medial aspect of the STN where a varying
degree of overlaps are apparent between the input zones (Fig. 2; see also [12,13,16,17].
In terms of the somatotopical representation, the corticostriatal input zones from regions of the
frontal motor-related areas (i.e., the MI, SMA, and PM) representing the hindlimb, forelimb,
and orofacial part are, in this order, arranged from dorsal to ventral within the putamen (Fig.
3; see also [14]). A similar pattern is most likely to organize the somatotopical arrangement of
cortical motor inputs within the GPe and GPi (Fig. 3). Of particular interest is that dual sets of
body part representations underlie the somatotopical arrangement in the STN. Somatotopical
representations in the lateral part of the STN are arranged from medial to lateral in the order of
the hindlimb, forelimb, and orofacial part. By contrast, these body parts in the medial
counterpart are represented mediolaterally in the inverse order, as though reflecting a mirror
image against the somatotopical arrangement in the lateral STN (Fig. 3; see also [12]).
Figure 2. Summary diagram showing the organization of corticosubthalamic input zones from the
frontal motor-related areas. Broken arrows represent minor projections.
Figure 3. Corticobasal ganglia loop circuits arising from the frontal motor-related areas (i.e., the MI,
SMA, and PM) in terms of the somatotopical representation. Corticostriatal input zones from regions of
representing the hindlimb, forelimb, and orofacial part are, in this order, arranged from dorsal to
ventral within the putamen and GPe/GPi. In the STN, there exist dual sets of body part representations.
Somatotopical representations in the lateral STN are arranged from medial to lateral in the order of the
hindlimb, forelimb, and orofacial part, whereas the medial STN exhibits a mediolaterally reversed
pattern of the representations, thereby reflecting a mirror image against the somatotopical
arrangement in the lateral STN.

3. Organization of multisynaptic pathways linking F2 and the basal

ganglia
3.1. Rabies injections
Multiple injections of rabies virus were made into F2c and F2r in the PMd (Fig. 4). The
injection sites were determined according to the results of our previous electrophysiological
work in which we demonstrated that the neuronal response properties involved in planning
and executing reaching movements differed in F2r and F2c [20]. This rostrocaudal
segregation is consistent with the classification schema that emerged in previous studies
[10,21,22]. The rabies injections were carried out lateral to the superior precentral dimple for
the F2c procedure (Fig. 4B). For the F2r procedure, on the other hand, the rabies injections
were done around the genu of the arcuate sulcus (Fig. 4C).
Figure 4. Locations of the injection sites in F2c and F2r. (A) Diagram illustrating the macaque lateral
frontal lobe. The rectangular area drawn with broken lines in (A) is enlarged in (B) and (C). (B,C)
Injection sites of rabies virus in F2c (B) and F2r (C). In (B) and (C), the border between the PMd/PMv
and the MI is represented with the broken line. AS, arcuate sulcus; CS, central sulcus; Dimple, superior
precentral dimple; Genu, genu of the AS; PS, principal sulcus; Spur, spur of the AS.
3.2. Origins of basal ganglia inputs to F2c and F2r

Three days after the rabies injection into F2c or F2r, a number of labeled neurons were
observed in the GPi and SNr. These neurons are considered to send outputs to F2c or F2r via
the ventral nuclei or mediodorsal nucleus of the thalamus. No labeled neurons were found
in the GPe at this stage, indicating that only the second-order neuron labeling occurred at
the 3-day postinjection period.
The distribution of labeled neurons observed in the GPi after the F2c injection differed from
that observed after the F2r injection (Fig. 5). Two-dimensional density maps of the GPi were
prepared to separately represent the labeling patterns in outer and inner portions (Fig. 5A).
These maps showed that the distributions of GPi neurons projecting to F2c and F2r were
segregated in both portions, each of which received input from the striatum [23]. After the
F2c injection, the labeled neurons were distributed broadly in the ventral part of the GPi at
its caudal level (Fig. 5B). By contrast, the labeled neurons after the F2r injection were located
in the dorsal part of the GPi at its rostocaudal middle level (Fig. 5C).
Figure 5. Density maps of GPi neuron labeling after rabies injections into F2c and F2r. (A) Procedures
to construct two-dimensional density maps of the GPi. The unfolding process started with drawing
lines through the center of the outer (oGPi) and inner (iGPi) portions of the GPi (left). The reference
points were placed at the bottom (specified by pink stars or red circles) and the top (specified by cyan
triangles or blue squares) of the GPi. The position of each labeled neuron was projected onto the central
line. Then, each line through the nucleus was aligned on the ventral edge of the GPi (right). The GPi
was divided into 300 m x 300 m bins. (B) Density maps of oGPi and iGPi neuron labeling after F2c
injection. (C) Density maps of oGPi and iGPi neuron labeling after F2r injection. The number of labeled
neurons in each bin was counted and color-coded.

The rabies injections into F2c and F2r resulted in different distributions of neuronal labeling
in the SNr. After the F2c injection, labeled neurons in the SNr were found in the central part
through the caudal half of the SNr. After the F2r injection, on the other hand, labeled
neurons were distributed primarily throughout the rostral half of the SNr (data not shown).
By extending the postinjection period to 4 days, we detected neuronal labeling in the GPe,
STN, and striatum. In the GPe, labeled neurons were widely distributed over the nucleus
following the F2c injection, whereas they occupied a more restricted area following the F2r
injection (Fig. 6). To compare the two distribution patterns in detail, two-dimensional
density maps of the GPe were prepared to depict the results from the F2c and F2r injections
(Fig. 6A). In the F2r injection case, the labeled neurons were located only in the rostral and
dorsal portions of the GPe (Fig. 6C), while those in the F2c injection case were found not
only in the rostral and dorsal portions, but also in the caudal and ventral portions of the GPe
(Fig. 6B). These data indicated that the area in which GPe neurons projected trisynaptically
to F2r was included within the area in which GPe neurons projected to F2c.
Figure 6. Density maps of GPe neuron labeling after rabies injections into F2c and F2r. (A) Procedures
to construct two-dimensional density maps of the GPe. The unfolding process started with drawing
lines through the center of the GPe (top). The reference points were placed at the bottom (specified by
red stars) and the top (specified by blue triangles) of the GPe. The position of each labeled neuron was
projected onto the central line. Then, each line through the nucleus was aligned on the ventral edge of
the GPe (bottom). The GPe was divided into 300 m x 300 m bins. (B) Density map of GPe neuron
labeling after F2c injection. (C) Density map of GPe neuron labeling after F2r injection. The number of
labeled neurons in each bin was counted and color-coded.
In Figure 7, density maps of neuronal labeling in the STN are shown. After the F2r injection,
labeled neurons were located primarily in the ventral aspect (Fig. 7, lower row), whereas the
area of rabies labeling after the F2c injection expanded more dorsally (Fig. 7, upper row).
Figure 7. Distributions of STN neuron labeling after rabies injections into F2c and F2r. Three
equidistant coronal sections are arranged rostrocaudally in a-c (after F2c injection) and a-c (after F2r
injection). The STN was divided into 300 m x 300 m bins. The number of labeled neurons in each bin
was counted and color-coded.
Large numbers of labeled neurons were observed in the striatum. Following each injection,
the labeled neurons were widely distributed in the striatal cell bridges and their neighboring
regions of the caudate nucleus and the putamen (Fig. 8). In addition, dense neuron labeling
was seen in the ventral striatum (Fig. 8).

Figure 8. Distributions of striatal neuron labeling after rabies injections into F2c and F2r. Six
equidistant coronal sections are arranged rostrocaudally in a-f (after F2c injection) and a-f (after F2r
injection). The striatum was divided into 500 m x 500 m bins. The number of labeled neurons in
each bin was counted and color-coded. ac, anterior commissure; Cd, caudate nucleus; Put, putamen.
4. Conclusion
Here, we propose that two separate channels, each of which projects multisynaptically to
F2c and F2r, may be operated in the output stations of the basal ganglia (i.e., the GPi and
SNr), although segregation may be obscured in the input station (i.e., the striatum) where
neurons projecting multisynaptically to F2c and F2r intermingle (Fig. 9). This indicates that
each of the two parallel loops (i.e., the F2c-basal ganglia loop and the F2r-basal ganglia loop)
Figure 9. Schematic diagram showing the distribution patterns of cells of origin in the basal ganglia of
multisynaptic inputs to F2c and F2r. In the striatum, GPe/STN, and GPi/SNr, open and filled circles
indicate neurons projecting multisynaptically to F2c and F2r, respectively. In the output stations of the
basal ganglia (i.e., GPi/SNr), the cells of origin of multisynaptic projections to F2c and F2r are basically
segregated. On the other hand, intermingling rather than segregation is prominent for the other basal
ganglia components, including the input station (i.e., striatum). Note that in the GPe/STN that connects
the input and output stations, the F2r territory tends to be included within the F2c territory (see the text
for detail). Ass, association cortical areas such as the prefrontal cortex; Mot, motor cortical areas such as
the MI and SMA; Th, thalamus.

collects diverse inputs from the motor and association territories with which F2c and F2r are
cortically interconnected. Given that individual neurons in the GPi and SNr have
widespread dendritic trees [24,25], these structures may consist of zones where diverse
inputs are sorted and integrated, which allows each structure to send outputs to F2c and F2r
separately. On the other hand, the distribution pattern of neurons in the GPe and STN that
project multisynaptically to F2c and F2r differs from that of neurons in the GPi and SNr; the
F2r territory seems to be included within the F2c territory in the GPe and STN. This suggests
that the mode of information processing in the GPe and STN may be distinct from that in
the GPi and SNr. Together with a previous notion that there is the precise network
architecture in each component of the basal ganglia [26-28], our overall results will provide a
novel framework for understanding the mode of information processing in the corticobasal
ganglia loop circuits.
By analyzing the network linking F2 and the cerebellum, we have revealed that the cells of
origin in the cerebellum of multisynaptic projections to F2c and F2r are segregated at the
output station (i.e., the deep cerebellar nuclei), whereas both integration and segregation are
evident at the input station (i.e., the cerebellar cortex) [11]. The networks connecting the
basal ganglia/cerebellum with F2 may be governed by a common rule organizing the
segregation at the output stage and the intermingling rather than the segregation at the
input stage.
Author details
Masahiko Takada* and Ken-ichi Inoue
Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama,
Japan
Masahiko Takada, Eiji Hoshi and Atsushi Nambu
Japan Science and Technology Agency, CREST, Tokyo,
Japan
Eiji Hoshi and Yosuke Saga
Frontal Lobe Project, Tokyo Metropolitan Institute of Medical Science, Tokyo,
Japan
Shigehiro Miyachi
Cognitive Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama,
Japan
Nobuhiko Hatanaka and Atsushi Nambu
Division of System Neurophysiology, National Institute for Physiological Sciences and Department
of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki,
Japan
*
Corresponding Author
Masahiko Inase
Department of Physiology, Kinki University School of Medicine, Osaka-Sayama,
Japan
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BASAL GANGLIA

Basal Ganglia An Integrative View

Publishing Process Manager Dragana Manestar

Clinical Motor and Cognitive Neurobehavioral

Fetal and Environmental Basis for

Basal Ganglia and the Error Monitoring and Processing

The Integrative Role of the Basal Ganglia 87

Organization of Two CorticoBasal Ganglia Loop

Clinical Motor and Cognitive Neurobehavioral

2. The basal ganglia in the context of behavior

2 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 3

4 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 5

3. Direct and indirect pathways

6 Basal Ganglia An Integrative View

Functional Organization of the Basal Ganglia

Direct Pathway: Increases motor output

Figure 4. Direct and Indirect pathways. Direct pathway runs: CortexstriatumGPi

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 7

4. Clinical behavioral implications of pathway activity balance

8 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 9

10 Basal Ganglia An Integrative View

A functional imbalance and/or a functional disconnection between the two hemispheres,

5. Dynamic inter-regional effects

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 11

12 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 13

7. Basal ganglia in obsessive compulsive disorder

14 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 15

16 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 17

8. Basal ganglia in tourettes syndrome

18 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 19

9. Basal ganglia in ADHD

20 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 21

22 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 23

24 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 25

26 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 27

Microstructure in Adolescents with Obsessive-Compulsive Disorder. Biol psychiatry.

28 Basal Ganglia An Integrative View

Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia 29

30 Basal Ganglia An Integrative View

Fetal and Environmental Basis for

32 Basal Ganglia An Integrative View

2. Major symptoms and the proposed causes for Parkinsons disease

Fetal and Environmental Basis for the Cause of Parkinsons Disease 33

mitochondrial abnormalities, excitotoxins, over exposure to manganese (Chu et al, 1995;

2.1. Aberrations in non-basal ganglia systems

3. The fetal basis hypothesis for Parkinsons disease

34 Basal Ganglia An Integrative View

3.1. Chance encounter of the nigrostriatal neurons with harmful factors